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Clinical Trial Results:
A phase II, randomized, active-controlled, multicenter study comparing the efficacy and safety of targeted therapy or cancer immunotherapy guided by genomic profiling versus platinum-based chemotherapy in patients with cancer of unknown primary site who have received three cycles of platinum doublet chemotherapy

Summary
EudraCT number	2017-003040-20
Trial protocol	GB AT EE IE DE CZ FI LV HU PL FR ES BG PT HR NO NL DK CY IT RO
Global end of trial date

Results information
Results version number	v1
This version publication date	06 Mar 2024
First version publication date	06 Mar 2024
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

MX39795

ISRCTN number

US NCT number

NCT03498521

WHO universal trial number (UTN)

Sponsor organisation name

Hoffmann-La Roche

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, 4070

Public contact

F. Hoffmann-La Roche AG, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Interim

Date of interim/final analysis

14 Feb 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

14 Feb 2023

Global end of trial reached?

Main objective of the trial

Study MX39795 compared the efficacy and safety of molecularly-guided therapy versus standard platinum-containing chemotherapy in patients with poor prognosis cancer of unknown primary site (CUP; non-specific subset) who have achieved disease control (CR, PR or SD) after 3 cycles of first-line platinum-based induction chemotherapy. Molecularly-guided therapies included 10 targeted cancer therapy regimens and 2 cancer immunotherapy regimens and were chosen based on each participant's comprehensive genomic profile.

Protection of trial subjects

All participants were required to sign an Informed Consent Form

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Apr 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 24

Country: Number of subjects enrolled

Austria: 3

Country: Number of subjects enrolled

Bulgaria: 3

Country: Number of subjects enrolled

Brazil: 29

Country: Number of subjects enrolled

Switzerland: 4

Country: Number of subjects enrolled

Chile: 8

Country: Number of subjects enrolled

Colombia: 6

Country: Number of subjects enrolled

Czechia: 17

Country: Number of subjects enrolled

Germany: 65

Country: Number of subjects enrolled

Denmark: 4

Country: Number of subjects enrolled

Spain: 54

Country: Number of subjects enrolled

Estonia: 3

Country: Number of subjects enrolled

Finland: 6

Country: Number of subjects enrolled

France: 50

Country: Number of subjects enrolled

United Kingdom: 59

Country: Number of subjects enrolled

Greece: 15

Country: Number of subjects enrolled

Croatia: 2

Country: Number of subjects enrolled

Hungary: 4

Country: Number of subjects enrolled

Ireland: 7

Country: Number of subjects enrolled

Israel: 11

Country: Number of subjects enrolled

Italy: 22

Country: Number of subjects enrolled

Japan: 13

Country: Number of subjects enrolled

Korea, Republic of: 22

Country: Number of subjects enrolled

Latvia: 6

Country: Number of subjects enrolled

Mexico: 6

Country: Number of subjects enrolled

Netherlands: 12

Country: Number of subjects enrolled

Norway: 5

Country: Number of subjects enrolled

Peru: 2

Country: Number of subjects enrolled

Poland: 1

Country: Number of subjects enrolled

Portugal: 4

Country: Number of subjects enrolled

Romania: 12

Country: Number of subjects enrolled

Thailand: 8

Country: Number of subjects enrolled

Türkiye: 41

Worldwide total number of subjects

528

EEA total number of subjects

295

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

308

From 65 to 84 years

220

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

Eligible participants included adults with poor prognosis cancer of unknown primary site (CUP).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Molecularly-Guided Therapy MGT) Category 1

Arm description

Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). MGT was chosen based on each participant's comprehensive genomic profile and administered until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Entrectinib

Investigational medicinal product code

Other name

RO7102122

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Administered as recommended in its US label for patients with NTRK gene fusions or ROS1 gene rearrangements (600 mg QD) until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Alectinib

Investigational medicinal product code

Other name

RO5424802

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Administered as recommended for ALK-positive non-small cell lung cancer (NSCLC) (600 mg twice daily (BID) until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Erlotinib

Investigational medicinal product code

Other name

RO508231

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered as recommended in its EMA Summary of Product Characteristics (EU SmPC) for advanced NSCLC (150 mg per day (QD)) in combination with bevacizumab until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

RO5541267

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered alone or in combination with platinum-based chemotherapy as recommended for urinary carcinoma or NSCLC (1200 mg IV infusion over 60 min every three weeks (Q3W)) until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Vismodegib

Investigational medicinal product code

Other name

RO5450815

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Administered as recommended for metastatic basal cell carcinoma (150 mg QD) until loss of clinical benefit or toxicity.

Investigational medicinal product name

Pemigatinib

Investigational medicinal product code

Other name

RO7496200

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered as recommended for advanced or metastatic cholangiocarcinoma with FGFR2 fusions or other rearrangements (13.5 mg QD) across a 21-day treatment cycle until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Olaparib

Investigational medicinal product code

Other name

RO5508245

Pharmaceutical forms

Capsule, Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Administered as recommended for patients with germline BRCA-mutated advanced ovarian cancer (400 mg twice-daily (BID) for capsules, or 300 mg BID for film-coated tablets) until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Ivosidenib

Investigational medicinal product code

Other name

RO7499824

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered as recommended in its US label for patients with newly-diagnosed or relapsed/refractory acute myeloid leukemia with a susceptible IDH1 mutation (500 mg QD across a 28-day treatment cycle) until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

RO0247506

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered at a dose of 175 mg/m^2 on Day 1 as part of platinum-based chemotherapy at induction (3 cycles) for all participants, then for a minimum of an additional 3 cycles for selected participants.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

RO0232538

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered at a dose of 60-75 mg/m^2 on Day 1 as part of platinum-based chemotherapy at induction (3 cycles) for all participants, then for a minimum of an additional 3 cycles for selected participants.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

RO4843791

Pharmaceutical forms

Solution for injection, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered weekly as part of platinum-based chemotherapy at induction (3 cycles) at an AUC dose calculated by the Calvert formula for all participants, then for a minimum of an additional 3 cycles for selected participants.

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

Other name

RO4368451

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered as recommended for advanced breast cancer with HER2 alterations (initial loading dose of 840 mg; thereafter 420 mg Q3W) in combination with trastuzumab and platinum-based chemotherapy.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

RO0452317

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered as recommended for advanced breast cancer with HER2 alterations (600 mg fixed-dose SC injection Q3W) in combination with pertuzumab and platinum-based chemotherapy.

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

RO5514041

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered as recommended in its investigator's brochure for advanced melanoma (60 mg QD for the first 21 days of a 28-Day treatment cycle) in combination with vemurafenib until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Vemurafenib

Investigational medicinal product code

Other name

RO5185426

Pharmaceutical forms

Film-coated tablet and gastro-resistant granules in sachet, Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Administered as recommended in its investigator's brochure for advanced melanoma (960 mg BID) in combination with cobimetinib until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

RO0247506

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered at a dose of 80 mg/m^2 on Days 1, 8, and 15 of a 28-Day cycle for 3 cycles in combination with ipatasertib.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

RO0249587

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered at a dose of 1000 mg/m^2 on Day 1 and Day 8 of a 3-week cycle as part of platinum-based chemotherapy at induction (3 cycles) for all participants, then for a minimum of an additional 3 cycles for selected participants.

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

RO4876646

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered as recommended in its EU SmPC for advanced NSCLC (15 mg/kg Q3W) in combination with erlotinib until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Ipatasertib

Investigational medicinal product code

Other name

RO5532961

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered at a dose of 400 mg QD on Days 1-21 of a 28-day cycle, first in combination with paclitaxel (3 cycles) and then as monotherapy until loss of clinical benefit or unacceptable toxicity.

Chemotherapy Category 1

Arm description

Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.

Arm type

Control

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

RO4843791

Pharmaceutical forms

Solution for injection, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

RO0249587

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

RO0232538

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

RO0247506

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Category 2

Arm description

Category 2 included participants with progressive disease (PD) after 3 cycles of platinum induction chemotherapy. Participants in this arm received either MGT based on their comprehensive genomic profile until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first, or the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.

Arm type

Experimental

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

RO4843791

Pharmaceutical forms

Solution for injection, Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

RO0247506

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

RO5541267

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Vismodegib

Investigational medicinal product code

Other name

RO5450815

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Administered as recommended for metastatic basal cell carcinoma (150 mg QD) until loss of clinical benefit or toxicity.

Investigational medicinal product name

Pemigatinib

Investigational medicinal product code

Other name

RO7496200

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Olaparib

Investigational medicinal product code

Other name

RO5508245

Pharmaceutical forms

Capsule, Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Ivosidenib

Investigational medicinal product code

Other name

RO7499824

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Entrectinib

Investigational medicinal product code

Other name

RO7102122

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Administered as recommended in its US label for patients with NTRK gene fusions or ROS1 gene rearrangements (600 mg QD) until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Alectinib

Investigational medicinal product code

Other name

RO5424802

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Administered as recommended for ALK-positive non-small cell lung cancer (NSCLC) (600 mg twice daily (BID) until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

RO0232538

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

RO0249587

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Vemurafenib

Investigational medicinal product code

Other name

RO5185426

Pharmaceutical forms

Film-coated tablet and gastro-resistant granules in sachet, Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Administered as recommended in its investigator's brochure for advanced melanoma (960 mg BID) in combination with cobimetinib until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

RO0247506

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered at a dose of 80 mg/m^2 on Days 1, 8, and 15 of a 28-Day cycle for 3 cycles in combination with ipatasertib.

Investigational medicinal product name

Ipatasertib

Investigational medicinal product code

Other name

RO5532961

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Administered at a dose of 400 mg QD on Days 1-21 of a 28-day cycle, first in combination with paclitaxel (3 cycles) and then as monotherapy until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

RO4876646

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered as recommended in its EU SmPC for advanced NSCLC (15 mg/kg Q3W) in combination with erlotinib until loss of clinical benefit or unacceptable toxicity.

Investigational medicinal product name

Erlotinib

Investigational medicinal product code

Other name

RO508231

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

RO0452317

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered as recommended for advanced breast cancer with HER2 alterations (600 mg fixed-dose SC injection Q3W) in combination with pertuzumab and platinum-based chemotherapy.

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

RO5514041

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

Other name

RO4368451

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered as recommended for advanced breast cancer with HER2 alterations (initial loading dose of 840 mg; thereafter 420 mg Q3W) in combination with trastuzumab and platinum-based chemotherapy.

Number of subjects in period 1	Molecularly-Guided Therapy MGT) Category 1	Chemotherapy Category 1	Category 2
Started	326	110	92
Completed	0	0	0
Not completed	326	110	92
Adverse event, serious fatal	191	64	72
No profile due to technical failure	1	-	-
Consent withdrawn by subject	9	6	2
Study ongoing	121	36	15
Physician decision	-	1	-
Lost to follow-up	3	3	3
Exclusion criteria	1	-	-

Baseline characteristics

Top of page

Reporting group title

Molecularly-Guided Therapy MGT) Category 1

Reporting group description

Reporting group title

Chemotherapy Category 1

Reporting group description

Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.

Reporting group title

Category 2

Reporting group description

Reporting group values	Molecularly-Guided Therapy MGT) Category 1	Chemotherapy Category 1	Category 2	Total
Number of subjects	326	110	92	528
Age categorical
Units: Subjects
Adults (18-64 years)	188	61	59	308
From 65-84 years	138	49	33	220
Age Continuous
Units: Years
arithmetic mean (standard deviation)	60.5 ( 11.5 )	61.1 ( 11.3 )	59.4 ( 12.7 )	-
Sex: Female, Male
Units: Participants
Female	161	53	43	257
Male	165	57	49	271
Race, Customized
Units: Subjects
American Indian or Alaska Native	4	3	1	8
Asian	31	12	7	50
Black or African American	5	0	0	5
Unknown	43	14	15	72
White	242	81	69	392
Missing	1	0	0	1
Ethnicity, Customized
Units: Subjects
Hispanic or Latino	22	9	4	35
Not Hispanic or Latino	252	85	75	412
Not Stated	31	11	7	49
Unknown	21	5	6	32

End points

Top of page

Reporting group title

Molecularly-Guided Therapy MGT) Category 1

Reporting group description

Reporting group title

Chemotherapy Category 1

Reporting group description

Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.

Reporting group title

Category 2

Reporting group description

Primary: Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1)

Top of page

End point title

Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) ^[1]

End point description

This efficacy objective was to evaluate the efficacy of MGT vs platinum chemotherapy in term of PFS in participants with CUP whose best response to 3 cycles of platinum induction chemotherapy was assessed CR, PR, or SD.

End point type

Primary

End point timeframe

From randomization to the first occurrence of disease progression or death from any cause, until 330 PFS events were observed (approx. 4.3 years for MGT Cat 1 and 3.4 years for Chemotherapy Cat 1).

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was specific to Category 1 arms. Category 2 endpoints were exploratory and not included in analysis.

End point values	Molecularly-Guided Therapy MGT) Category 1	Chemotherapy Category 1
Number of subjects analysed	326	110
Units: Months
median (confidence interval 95%)	6.05 (4.70 to 6.47)	4.40 (4.14 to 5.59)

PFS ITT Category 1

Comparison groups

Molecularly-Guided Therapy MGT) Category 1 v Chemotherapy Category 1

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0079

Method

Stratified log-rank

Parameter type

Stratified Cox proportional hazard

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

0.92

Secondary: Overall Survival (OS)

Top of page

End point title

Overall Survival (OS) ^[2]

End point description

The intent-to-treat (ITT) population included all Category 1 randomized participants, whether or not the assigned study treatment was received. Endpoints for Category 2 were exploratory and were not included in this analysis.

End point type

Secondary

End point timeframe

From randomization to death from any cause, through the end of study (approximately 4 years)

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was specific to Category 1 arms. Category 2 endpoints were exploratory and not included in analysis.

End point values	Molecularly-Guided Therapy MGT) Category 1	Chemotherapy Category 1
Number of subjects analysed	189	64
Units: Months
median (confidence interval 95%)	14.65 (13.31 to 17.25)	11.04 (9.72 to 15.38)

No statistical analyses for this end point

Secondary: Objective Response Rate (ORR)

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End point title

Objective Response Rate (ORR) ^[3]

End point description

End point type

Secondary

End point timeframe

Two consecutive occurrences of complete or partial response >/=4 weeks apart

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was specific to Category 1 arms. Category 2 endpoints were exploratory and not included in analysis.

End point values	Molecularly-Guided Therapy MGT) Category 1	Chemotherapy Category 1
Number of subjects analysed	326 ^[4]	110 ^[5]
Units: Percentage of participants
number (confidence interval 95%)
Complete response (CR)	4.9 (2.83 to 7.85)	3.6 (1.00 to 9.05)
Partial response (PR)	12.9 (9.45 to 17.01)	4.5 (1.49 to 10.29)
Stable disease (SD)	44.5 (39.00 to 50.06)	49.1 (39.43 to 58.80)
Non-CR/Non-PD	7.1 (4.52 to 10.40)	6.4 (2.60 to 12.67)
NA	2.5 (1.07 to 4.78)	2.7 (0.57 to 7.76)
Progressive disease (PD)	17.8 (13.80 to 22.38)	21.8 (14.51 to 30.70)
Not evaluable	0.6 (-9999 to 9999)	0 (-9999 to 9999)
Missing	9.8 (-9999 to 9999)	11.8 (-9999 to 9999)

Notes
[4] - 9999 values indicate not evaluable or missing data
[5] - 9999 values indicate not evaluable or missing data

No statistical analyses for this end point

Secondary: Duration of Response (DOR)

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End point title

Duration of Response (DOR) ^[6]

End point description

End point type

Secondary

End point timeframe

From the first documentation of a complete response (CR) or partial response (PR) to disease progression or death from any cause, whichever occurs first (up to approximately 70 months)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was specific to Category 1 arms. Category 2 endpoints were exploratory and not included in analysis.

End point values	Molecularly-Guided Therapy MGT) Category 1	Chemotherapy Category 1
Number of subjects analysed	58 ^[7]	9 ^[8]
Units: Months
median (confidence interval 95%)	16.39 (8.08 to 9999)	9999 (4.14 to 9999)

Notes
[7] - 9999 = Value is NA due to insufficient no. of participants with the event.
[8] - 9999 = Value is NA due to insufficient no. of participants with the event.

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR1)

Top of page

End point title

Disease Control Rate (DCR1) ^[9]

End point description

End point type

Secondary

End point timeframe

From randomization to death from any cause, through the end of study (approximately 70 months)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was specific to Category 1 arms. Category 2 endpoints were exploratory and not included in analysis.

End point values	Molecularly-Guided Therapy MGT) Category 1	Chemotherapy Category 1
Number of subjects analysed	326	110
Units: Percentage of responders
number (confidence interval 95%)	64.7 (59.27 to 69.91)	60.0 (50.22 to 69.22)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Approximately 4.5 years

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Molecularly-Guided Therapy

Reporting group description

Reporting group title

Category 2

Reporting group description

Reporting group title

Chemotherapy

Reporting group description

Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles.

Serious adverse events	Molecularly-Guided Therapy	Category 2	Chemotherapy
Total subjects affected by serious adverse events
subjects affected / exposed	112 / 312 (35.90%)	37 / 92 (40.22%)	14 / 101 (13.86%)
number of deaths (all causes)	185	72	58
number of deaths resulting from adverse events	14	12	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cholangiocarcinoma
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatic adenoma
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 312 (0.00%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vena cava thrombosis
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pain
subjects affected / exposed	1 / 312 (0.32%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 312 (0.32%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 312 (0.32%)	1 / 92 (1.09%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	1 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	3 / 312 (0.96%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 1	0 / 0
Pyrexia
subjects affected / exposed	7 / 312 (2.24%)	2 / 92 (2.17%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 8	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	3 / 312 (0.96%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 312 (0.32%)	2 / 92 (2.17%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	4 / 312 (1.28%)	0 / 92 (0.00%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	1 / 4	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Psychiatric decompensation
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anxiety
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Hepatic enzyme increased
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Hip fracture
subjects affected / exposed	1 / 312 (0.32%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stoma site haemorrhage
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 312 (0.00%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocarditis noninfective
subjects affected / exposed	0 / 312 (0.00%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 312 (0.00%)	3 / 92 (3.26%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 312 (0.00%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune-mediated encephalitis
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mononeuritis
subjects affected / exposed	0 / 312 (0.00%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myasthenic syndrome
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vestibular migraine
subjects affected / exposed	0 / 312 (0.00%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 312 (0.00%)	2 / 92 (2.17%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Syncope
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	2 / 312 (0.64%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	4 / 312 (1.28%)	5 / 92 (5.43%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	2 / 4	5 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombotic microangiopathy
subjects affected / exposed	0 / 312 (0.00%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Agranulocytosis
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	4 / 312 (1.28%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 312 (0.00%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Autoimmune haemolytic anaemia
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Periorbital oedema
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	4 / 4	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal incarcerated hernia
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal ulcer perforation
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	6 / 312 (1.92%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	5 / 8	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenitis
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Neutropenic colitis
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumatosis intestinalis
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 312 (0.00%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gallbladder rupture
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholestasis
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash maculo-papular
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pruritus
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	2 / 101 (1.98%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 312 (0.00%)	2 / 92 (2.17%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Endocrine disorders
Secondary adrenocortical insufficiency
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperthyroidism
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Urinary tract infection
subjects affected / exposed	6 / 312 (1.92%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 6	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Sepsis
subjects affected / exposed	3 / 312 (0.96%)	4 / 92 (4.35%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 3	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 0
Pneumonia
subjects affected / exposed	5 / 312 (1.60%)	1 / 92 (1.09%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	2 / 5	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	1 / 312 (0.32%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	6 / 312 (1.92%)	2 / 92 (2.17%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 0
Anal abscess
subjects affected / exposed	1 / 312 (0.32%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Campylobacter gastroenteritis
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abscess jaw
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal infection
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal abscess
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 312 (0.00%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 312 (0.64%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis salmonella
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	3 / 312 (0.96%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyonephrosis
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal abscess
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection fungal
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal sepsis
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 312 (0.00%)	1 / 92 (1.09%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Type 1 diabetes mellitus
subjects affected / exposed	1 / 312 (0.32%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Molecularly-Guided Therapy	Category 2	Chemotherapy
Total subjects affected by non serious adverse events
subjects affected / exposed	276 / 312 (88.46%)	73 / 92 (79.35%)	79 / 101 (78.22%)
Vascular disorders
Hypertension
subjects affected / exposed	18 / 312 (5.77%)	0 / 92 (0.00%)	2 / 101 (1.98%)
occurrences all number	24	0	2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	57 / 312 (18.27%)	14 / 92 (15.22%)	15 / 101 (14.85%)
occurrences all number	76	16	19
Fatigue
subjects affected / exposed	65 / 312 (20.83%)	19 / 92 (20.65%)	13 / 101 (12.87%)
occurrences all number	99	25	17
Oedema peripheral
subjects affected / exposed	22 / 312 (7.05%)	7 / 92 (7.61%)	3 / 101 (2.97%)
occurrences all number	27	7	6
Pyrexia
subjects affected / exposed	26 / 312 (8.33%)	10 / 92 (10.87%)	3 / 101 (2.97%)
occurrences all number	42	10	5
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	21 / 312 (6.73%)	0 / 92 (0.00%)	4 / 101 (3.96%)
occurrences all number	31	0	4
Cough
subjects affected / exposed	22 / 312 (7.05%)	0 / 92 (0.00%)	3 / 101 (2.97%)
occurrences all number	37	0	3
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 312 (0.00%)	5 / 92 (5.43%)	0 / 101 (0.00%)
occurrences all number	0	5	0
Investigations
Neutrophil count decreased
subjects affected / exposed	32 / 312 (10.26%)	8 / 92 (8.70%)	9 / 101 (8.91%)
occurrences all number	55	20	12
Weight decreased
subjects affected / exposed	18 / 312 (5.77%)	6 / 92 (6.52%)	3 / 101 (2.97%)
occurrences all number	18	7	3
Platelet count decreased
subjects affected / exposed	37 / 312 (11.86%)	9 / 92 (9.78%)	8 / 101 (7.92%)
occurrences all number	73	11	17
Alanine aminotransferase increased
subjects affected / exposed	16 / 312 (5.13%)	0 / 92 (0.00%)	7 / 101 (6.93%)
occurrences all number	23	0	7
Aspartate aminotransferase increased
subjects affected / exposed	17 / 312 (5.45%)	0 / 92 (0.00%)	6 / 101 (5.94%)
occurrences all number	20	0	6
White blood cell count decreased
subjects affected / exposed	0 / 312 (0.00%)	6 / 92 (6.52%)	0 / 101 (0.00%)
occurrences all number	0	7	0
Nervous system disorders
Headache
subjects affected / exposed	17 / 312 (5.45%)	0 / 92 (0.00%)	3 / 101 (2.97%)
occurrences all number	18	0	5
Neuropathy peripheral
subjects affected / exposed	35 / 312 (11.22%)	0 / 92 (0.00%)	14 / 101 (13.86%)
occurrences all number	42	0	17
Peripheral sensory neuropathy
subjects affected / exposed	21 / 312 (6.73%)	0 / 92 (0.00%)	7 / 101 (6.93%)
occurrences all number	25	0	8
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	105 / 312 (33.65%)	35 / 92 (38.04%)	30 / 101 (29.70%)
occurrences all number	160	49	37
Leukopenia
subjects affected / exposed	12 / 312 (3.85%)	5 / 92 (5.43%)	9 / 101 (8.91%)
occurrences all number	19	5	13
Neutropenia
subjects affected / exposed	59 / 312 (18.91%)	11 / 92 (11.96%)	23 / 101 (22.77%)
occurrences all number	90	13	38
Thrombocytopenia
subjects affected / exposed	47 / 312 (15.06%)	13 / 92 (14.13%)	13 / 101 (12.87%)
occurrences all number	75	20	23
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	73 / 312 (23.40%)	8 / 92 (8.70%)	5 / 101 (4.95%)
occurrences all number	109	10	7
Nausea
subjects affected / exposed	81 / 312 (25.96%)	21 / 92 (22.83%)	19 / 101 (18.81%)
occurrences all number	114	29	32
Vomiting
subjects affected / exposed	38 / 312 (12.18%)	8 / 92 (8.70%)	12 / 101 (11.88%)
occurrences all number	54	9	16
Constipation
subjects affected / exposed	39 / 312 (12.50%)	11 / 92 (11.96%)	12 / 101 (11.88%)
occurrences all number	49	11	13
Abdominal pain
subjects affected / exposed	33 / 312 (10.58%)	9 / 92 (9.78%)	3 / 101 (2.97%)
occurrences all number	38	10	3
Abdominal pain upper
subjects affected / exposed	18 / 312 (5.77%)	0 / 92 (0.00%)	5 / 101 (4.95%)
occurrences all number	20	0	5
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	33 / 312 (10.58%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences all number	44	0	2
Pruritus
subjects affected / exposed	25 / 312 (8.01%)	0 / 92 (0.00%)	0 / 101 (0.00%)
occurrences all number	34	0	0
Alopecia
subjects affected / exposed	23 / 312 (7.37%)	0 / 92 (0.00%)	1 / 101 (0.99%)
occurrences all number	23	0	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 312 (0.00%)	5 / 92 (5.43%)	0 / 101 (0.00%)
occurrences all number	0	5	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	22 / 312 (7.05%)	7 / 92 (7.61%)	2 / 101 (1.98%)
occurrences all number	24	8	3
Arthralgia
subjects affected / exposed	42 / 312 (13.46%)	0 / 92 (0.00%)	6 / 101 (5.94%)
occurrences all number	53	0	6
Myalgia
subjects affected / exposed	20 / 312 (6.41%)	0 / 92 (0.00%)	7 / 101 (6.93%)
occurrences all number	28	0	7
Pain in extremity
subjects affected / exposed	20 / 312 (6.41%)	0 / 92 (0.00%)	3 / 101 (2.97%)
occurrences all number	32	0	3
Bone pain
subjects affected / exposed	0 / 312 (0.00%)	5 / 92 (5.43%)	0 / 101 (0.00%)
occurrences all number	0	5	0
Infections and infestations
COVID-19
subjects affected / exposed	21 / 312 (6.73%)	5 / 92 (5.43%)	2 / 101 (1.98%)
occurrences all number	21	5	2
Urinary tract infection
subjects affected / exposed	23 / 312 (7.37%)	0 / 92 (0.00%)	5 / 101 (4.95%)
occurrences all number	25	0	6
Metabolism and nutrition disorders
Hypomagnesaemia
subjects affected / exposed	22 / 312 (7.05%)	0 / 92 (0.00%)	4 / 101 (3.96%)
occurrences all number	35	0	6
Decreased appetite
subjects affected / exposed	54 / 312 (17.31%)	11 / 92 (11.96%)	9 / 101 (8.91%)
occurrences all number	66	14	11
Hyponatraemia
subjects affected / exposed	0 / 312 (0.00%)	6 / 92 (6.52%)	0 / 101 (0.00%)
occurrences all number	0	6	0
Hypoalbuminaemia
subjects affected / exposed	0 / 312 (0.00%)	5 / 92 (5.43%)	0 / 101 (0.00%)
occurrences all number	0	5	0

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Were there any global substantial amendments to the protocol? Yes

06 May 2018

Amended eligibility criteria.

13 Jul 2018

Updated eligibility criteria.

05 Nov 2018

Amended eligibility criteria.

29 Jul 2019

Added a new treatment (entrectinib). Replaced ipatasertib monotherapy with ipatasertib + paclitaxel combination therapy. Amended eligibility criteria.

11 Feb 2020

Amended eligibility criteria. Added the option for additional chemotherapy for eligible participants. Re-added ipatasertib monotherapy for participants that had started ipatasertib monotherapy under previous protocol versions.

19 Feb 2021

Added pemigatinib and ivosidenib as treatments. Replaced duration of clinical benefit endpoint with duration of response (DOR) and disease control rate (DCR). Category 1 participants deemed ineligible for MGT were allowed to continue with platinum-based chemotherapy. Amended eligibility criteria.

16 Aug 2021

Change to olaparib dose and formulation. Amended eligibility criteria.

24 Jan 2022

Addition of efficacy analysis population for Category 2 participants.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Baseline characteristics

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Primary: Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1)

Primary: Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Objective Response Rate (ORR)

Secondary: Objective Response Rate (ORR)

Secondary: Duration of Response (DOR)

Secondary: Duration of Response (DOR)

Secondary: Disease Control Rate (DCR1)

Secondary: Disease Control Rate (DCR1)

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