Clinical Trials Register

Summary
EudraCT Number:	2017-005108-89
Sponsor's Protocol Code Number:	VHIO17002
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2018-06-29
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2017-005108-89

A.3

Full title of the trial

Basket of Baskets: A Modular, Open-label, Phase II, Multicentre Study To Evaluate Targeted Agents in Molecularly Selected Populations With Advanced Solid Tumors.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A modular multi-Basket trial to improve personalized medicine in cancer patients

A.3.2

Name or abbreviated title of the trial where available

VHIO17002 (UK)

A.4.1

Sponsor's protocol code number

VHIO17002

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Vall d’Hebron Institute of Oncology (VHIO)
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	F.Hoffmann-La Roche Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Vall d’Hebron Institute of Oncology (VHIO)
B.5.2	Functional name of contact point	Susana Munoz
B.5.3	Address:
B.5.3.1	Street Address	Cellex Building; Carrer Natzaret, 115-117
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08035
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34 932 543 450
B.5.6	E-mail	smunoz@vhio.net

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Tecentriq
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Products Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Tecentriq
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATEZOLIZUMAB
D.3.9.2	Current sponsor code	RO5541267
D.3.9.3	Other descriptive name	MPDL3280A
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Subjects with advanced solid tumor

E.1.1.1

Medical condition in easily understood language

Cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10065147
E.1.2	Term	Malignant solid tumor
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to evaluate the antitumor activity of each matched therapies in small subject populations as a signal finding study.
For Module I, the primary objective will be the overall response rate by RECIST 1.1 of atezolizumab in each of the arms of module.

E.2.2

Secondary objectives of the trial

To evaluate the clinical benefit of matching therapies in small patient populations.

Specific Secondary objective for Module 1:
To characterize the safety and tolerability of atezolizumab as assessed by the incidence and severity of adverse events.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Part A:
1. Subjects must have histologically or cytologically confirmed malignancy that is metastatic or unresectable, who have progressed to standard therapy, who are receiving a standard anticancer treatment but no subsequent approved treatment would be available upon progression, who are unable to receive standard therapy, or for whom standard therapy does not exist.
2. Subjects must have ECOG performance status of 0 or 1.
3. Subjects must be 18 year-old or older.
4. Subjects must have measurable disease according to RECIST 1.1.
5. Subjects must have enough tumor tissue for molecular analysis
• Subjects providing formalin-fixed paraffin embedded tissue (FFPE) must provide a minimum amount of tissue ranging from 20 to 28 slides depending on the sample tumor cellularity. If there is not enough archival tissue to meet this criterion, the subject must undergo a tumor biopsy.
• Subjects providing fresh frozen tissue (FFT) must provide 4 core biopsies or equivalent. FFT must be preferentially collected from a tumor biopsy; hence, patients must have disease amenable to be biopsied. Otherwise, the subject should have FFT stored in a biobank or biorepository.
• Efforts will be made to provide FFT in at least one quarter of the participating subjects. The proportion of subjects that might provide FFT might change based on the results from the molecular analysis.
• Since some of the tests are performed in FFPE tissue, patients providing FFT from a recent biopsy will have part of the sample processed in FFPE tissue as per Laboratory manual.
6. Subjects must have adequate hematological function: absolute granulocyte count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L.
7. Subject must have adequate renal and hepatic function: creatinine clearance ≥ 30ml/min, serum bilirubin ≤ 1.5 × ULN; unless due to Gilbert’s syndrome, AST/ALT ≤ 5 × ULN if liver metastases are present or AST/ALT ≤ 3 × ULN if
the subject has no liver involvement.
8. For subjects requiring a tumor biopsy: patients must have adequate
coagulation function quick time ≥ 60% or INR ≤ 1.5
9. Subjects must be willing to participate in a clinical trial with a matched therapy according to the molecular profile of his/her tumor
10.For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of <1% per year (when used consistently and correctly) during the treatment period and for at least 5 months after the last dose of atezolizumab, in case of being included in Part B of the study.Please see protocol for more details.
11.For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined in the protocol
12. Ability to understand and the willingness to sign a written informed consent document.
Part B:
Inclusion criterion 1/2/3/4 from part A
5. Subjects must be willing to participate in a clinical trial with a matched therapy according to the molecular profile of his/her tumor
6. Subjects must have adequate hematological function: absolute granulocyte count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L
7.Subjects must have adequate renal and hepatic function:
• Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: (140 − age) × (weight in kg) × (0.85 if female)/72 × (serum creatinine in mg/dL)
• Serum bilirubin ≤ 1.5 × ULN; with the following exception: subjects with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled
•AST,ALT, and alkaline phosphatase < 2.5 x ULN, with the following
exceptions:
oPatients with documented liver metastases:AST and ALT < 5 x ULN
oPatients with documented liver or bone metastases: alkaline phosphatase < 5 x ULN
8.Subjects receiving therapeutic anticoagulation (such as low−molecular weight heparin or warfarin) should be on a stable dose
9.For subjects requiring a tumor biopsy: subjects must have adequate coagulation function
•Quick time ≥ 60% or INR ≤ 1.5
10.Women of child-bearing potential and men must agree to use contraception: same as part A.
11. Ability to understand and the willingness to sign a written informed consent document.
12. Tumor must harbor the following alterations
• Arm 1A: BRCA1 or BRCA2 mutations
• Arm 1B: MLH1, MSH2, MSH6, or PMS2 mutations
• Arm 1C: tumors with POLE mutation, POLD1 mutation.
• Arm 1D: hypermutated tumors
• Subjects will be enrolled in this cohort if their tumors do not harbor any mutation required for arms 1A, 1B, 1C or 1F and their tumor mutational load meet the specified criteria.
i. High mutational load (>=16 mutation per Megabase as per FoundationOne test).
ii. Intermediate mutational load (12-<16 mutations per Megabase per FoundationOne test).
The definition of intermediate mutational load might be adjusted after an Interim analysis based on the avai

E.4

Principal exclusion criteria

Part A
1.Subjects with leptomeningeal disease should be excluded from this clinical trial.
2.Subjects with known unstable brain metastases should be excluded from this clinical trial.
•Exception: Subjects who have undergone surgery and/or radiotherapy and in which brain metastases remain stable or decrease in size for six months after having completed therapy.
3.Subjects with uncontrolled intercurrent illness
4.Subjects with inability to swallow tablets or capsules
5.Subjects with known HIV, hepatitis B or hepatitis C infection
6.Subjects with known history of malabsorption
7.Pregnant and lactating women. Females of childbearing potential must have a negative serum pregnancy test within 14 days prior to Day 1.
Part B:
1.Pregnant or breastfeeding women.This negative test will be valid for Cycle 1 day 1. In subsequent cycles, serum pregnancy test will be performed on day 1 of each cycle, with a +/- 3 day window, and prior to drug administration.
2.Any approved anticancer therapy within 3 weeks prior to initiation of study treatment.Exception:
•Hormone-replacement therapy or oral contraceptives;
•Somatostatin analogues for the treatment of symptoms related with neuroendocrine tumors.
•Gonadotropin-releasing hormone agonists or antiandrogens forprostate cancer.
•Palliative radiotherapy for bone metastases > 2 weeks prior to Cycle 1, Day 1.
3.Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the study
4.Treatment with an investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within five half-lives of the investigational product, whichever is longer), with the exception of monoclonal antibodies (4 week wash-out period)
5.Subjects with known unstable brain metastases. Exception: treated brain metastasis which remain stable or responding 6 weeks after completing radiotherapy
6.Uncontrolled intercurrent illness that would limit compliance with study requirements
7.Subjects with active hepatitis B (HBV) or hepatitis C (HCV). Subjects with past HBV infection or resolved HBV infection are eligible. Subjects positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA
8.Significant cardiovascular disease within 3 months prior to Cycle 1, Day 1, unstable arrhythmias or unstable angina.
Known left ventricular ejection fraction (LVEF) < 40% will be excluded. Known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
Uncontrolled effusion requiring recurrent drainage procedures; subjects with indwelling catheters are allowed.
Uncontrolled hypercalcemia (>1.5mmol/L ionized calcium or Ca > 12mg/dL or corrected serum calcium >ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
9.Another primary malignancy other than disease under study within 2 years prior to Cycle 1 Day 1, unless consider at low risk of relapse at Investigator discretion
10.Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD1, or anti−PDL1 therapeutic antibodies. Subjects who have received prior treatment with anti−CTLA-4 may be enrolled, provided at least 5 half-lives have elapsed from the last dose of anti-CTLA-4 to the first dose of Atezolizumab and there was no history of severe immune-mediated adverse effects from anti−CTLA-4
11.Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug (whichever is longer) prior to Cycle 1, Day 1
12.History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins, fusion proteins or any excipient of the experimental product.
13.History of active autoimmune disease in the last three years (unless exceptions)
14.Prior allogeneic bone marrow transplantation or prior solid organ transplantation

E.5 End points

E.5.1

Primary end point(s)

• Overall response rate (ORR) by RECIST 1.1 of different targeted agents in molecularly selected small patient populations.

Specific Primary Endpoint for Module 1
• Overall response rate by RECIST 1.1 of atezolizumab in each of the arms of module.

E.5.1.1

Timepoint(s) of evaluation of this end point

At Week 12

E.5.2

Secondary end point(s)

• Mean progression free survival (PFS by RECIST 1.1) of the patients participating in iBASKET evaluated at the end of the module.
• Progression Free Survival (PFS by RECIST 1.1) at 6 months of subjects treated with targeted therapy in iBASKET.
• Mean overall survival of subjects treated with targeted therapy in iBASKETevaluated at the end of the module.

Specific Secondary Endpoints for Module 1
• To evaluate the safety of atezolizumab in subjects with recurrent or metastatic solid tumors. Continued evaluation during the trial (Module 1).

Specific Secondary Endpoints for iPROFILER part.
•To determine the prevalence of genetic alterations in the iPROFILER screened population

E.5.2.1

Timepoint(s) of evaluation of this end point

- Mean progression free survival at the end of the module.
- Progression Free Survival at 6 months
- Mean overall survival at the end of the module
-Safety, continued evaluation during the trial

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

basket of basket study, modular study

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

End of the module will be considered 6 months after the last dose of the last participant patient in that specific module (after the Follow-up visit) or until all subjects have died, withdrawn consent or are lost to follow-up (whichever occurs first). A subject will be considered lost to follow up when reasonable attempts are made by the site to contact him/her without success.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1