Clinical Trials Register

Summary
EudraCT Number:	2019-001576-11
Sponsor's Protocol Code Number:	4010-03-001
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:	2020-03-16
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

2019-001576-11

A.3

Full title of the trial

A Phase 3, Randomized, Double-blind, Multicenter Study of Dostarlimab (TSR-042) plus Carboplatin-Paclitaxel versus Placebo plus Carboplatin-Paclitaxel in Patients with Recurrent or Primary Advanced Endometrial Cancer (RUBY)

A.3.1

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

A study to determine whether the addition of Dostarlimab (TSR-042) delays recurrence of advanced endometrial cancer

A.3.2

Name or abbreviated title of the trial where available

RUBY

A.4.1

Sponsor's protocol code number

4010-03-001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03981796

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	TESARO, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	TESARO, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	TESARO, Inc.
B.5.2	Functional name of contact point	RUBY Study Team
B.5.3	Address:
B.5.3.1	Street Address	1000 Winter Street, Suite 3300
B.5.3.2	Town/ city	Waltham
B.5.3.3	Post code	MA 02451
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 781 2572390
B.5.5	Fax number	+1 978 5138343
B.5.6	E-mail	Rubystudy@gsk.com

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	No
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	Dostarlimab
D.3.2	Product code	TSR-042
D.3.4	Pharmaceutical form	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	Dostarlimab
D.3.9.1	CAS number	2022215-59-2
D.3.9.2	Current sponsor code	TSR-042 and WBP-285
D.3.9.3	Other descriptive name	Anti-PD-1 (Programmed Cell Death Protein 1) monoclonal antibody, IgG4
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	50
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Recurrent or primary advanced (Stage III or IV) endometrial cancer

E.1.1.1

Medical condition in easily understood language

Endometrial cancer

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10014740
E.1.2	Term	Endometrial cancer stage III
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10014741
E.1.2	Term	Endometrial cancer stage IV
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the progression-free survival (PFS) of treatment with dostarlimab plus carboplatin-paclitaxel to treatment with placebo plus carboplatin-paclitaxel, as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1), in the following:
- All subjects with recurrent or primary advanced endometrial cancer
- Subjects with microsatellite instability-high (MSI-H) recurrent or primary advanced endometrial cancer

E.2.2

Secondary objectives of the trial

To evaluate the following measures of clinical benefit of treatment with dostarlimab plus carboplatin-paclitaxel compared to treatment with placebo plus carboplatin-paclitaxel in subjects with recurrent or primary advanced endometrial cancer:
- PFS based on blinded independent central review (BICR)
- Overall survival (OS)
- Objective response rate (ORR)
- Duration of response (DOR)
- Disease control rate (DCR)
- Patient-reported outcomes (PROs): European Quality of Life scale, 5-Dimensions, 5-Levels (EQ-5D-5L) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ-C30 [Core] and QLQ-EN24 [Endometrial Cancer Module])
To evaluate the safety and tolerability of dostarlimab plus carboplatin-paclitaxel compared to placebo plus carboplatin-paclitaxel.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Female subject at least 18 years of age, who is able to understand the study procedures and agrees to participate in the study by providing written informed consent.
2. Subject has histologically or cytologically proven endometrial cancer with recurrent or advanced disease.
3. Subject must provide adequate tumor tissue sample at Screening for MSI status testing.
4. Subject must have primary Stage III or Stage IV disease or first recurrent endometrial cancer with a low potential for cure by radiation therapy or surgery alone or in combination, and meet at least one of the following criteria:
a. Subject has primary Stage IIIA to IIIC1 disease with presence of evaluable or measurable disease per RECIST v.1.1 based on Investigator’s assessment. Lesions
that are equivocal or can be representative of postoperational change should be biopsied and confirmed for the presence of tumor.
b. Subject has primary Stage IIIC1 disease with carcinosarcoma, clear cell, serous, or mixed histology (containing ≥ 10% carcinosarcoma, clear cell, or serous histology) regardless of presence of evaluable or measurable disease on imaging.
c. Subject has primary Stage IIIC2 or Stage IV disease.
d. Subject has first recurrent disease and is chemotherapy naïve.
e. Subject has received prior neo-adjuvant/adjuvant systemic chemotherapy and had a recurrence or PD ≥ 6 months after completing treatment (first recurrence).
5. Subject has an ECOG performance status of 0 or 1.
6. Subject has adequate organ function, defined as follows:
a. Absolute neutrophil count ≥ 1,500 cells/μL b. Platelets ≥ 100,000 cells/μL c. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L d. Serum creatinine ≤ 1.5× upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 mL/min using the Cockcroft-Gault equation for subjects with creatinine levels > 1.5× institutional ULN
e. Total bilirubin ≤ 1.5× ULN and direct bilirubin ≤ 1× ULN
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5× ULN unless liver metastases are present, in which case they must be ≤ 5× ULN
g. International normalized ratio or prothrombin time (PT) ≤1.5× ULN and activated partial thromboplastin time ≤1.5× ULN. Subjects receiving anticoagulant therapy must have a PT or partial thromboplastin within the therapeutic range of intended use of anticoagulants.
7. Subject must have a negative serum pregnancy test within 72 hours of the first dose of study medication, unless they are of nonchildbearing potential. Nonchildbearing potential is defined as follows:
a. Postmenopausal (a woman who is ≥ 45 years of age and has not had menses for > 1 year).
b. A follicle-stimulating hormone value in the postmenopausal range upon screening evaluation if amenorrheic for < 2 years without a hysterectomy and oophorectomy
c. Posthysterectomy, postbilateral oophorectomy, or posttubal ligation.
- Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound, MRI, or CT scan.
- Tubal ligation must be confirmed with medical records of the actual procedure; otherwise, the subject must fulfill the criteria in Inclusion Criterion 8.
- Information must be captured appropriately within the site’s source documents.
8. Subjects of childbearing potential must be non-pregnant (see criterion above) and non-breast feeding, and must
agree to use at least 1 highly effective form of contraception or must not be heterosexually active starting with the Screening Visit through 180 days after the last dose of study treatment. The following are considered highly effective forms of contraception:
a. Hormonal contraceptives that include any registered and marketed contraceptive agent that contains an estrogen
and/or pregestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents),
b. Intrauterine device (IUD),
c. Vasectomized partner, and
d. Abstinence, is acceptable if this is the preferred and usual lifestyle of an individual.

E.4

Principal exclusion criteria

1. Subject has received neo-adjuvant/adjuvant systemic chemotherapy for primary Stage III or IV disease and:
a. has not had a recurrence or PD prior to entering the study OR
b. has had a recurrence or PD within 6 months of completing chemotherapy treatment prior to entering the study Note: Low-dose cisplatin given as a radiation sensitizer or hormonal therapies do not exclude subjects from study participation.
2. Subject has had > 1 recurrence of endometrial cancer.
3. Subject has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
4. Subject has received prior anticancer therapy (chemotherapy, targeted therapies, hormonal therapy, radiotherapy, or immunotherapy) within 21 days or < 5 times the half-life of the most recent therapy prior to Study Day 1, whichever is shorter.
5. Subject has a concomitant malignancy, or subject has a prior non-endometrial invasive malignancy who has been disease-free for < 3 years or who received any active treatment in the last 3 years for that malignancy. Non-melanoma skin cancer is allowed.
6. Subject has known uncontrolled central nervous system metastases, carcinomatosis meningitis, or both. Note: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of PD by imaging [using the identical imaging modality for each assessment, either MRI or CT scan] for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and have not been using steroids for at least 7 days prior to study treatment. Carcinomatous meningitis precludes a subject from study participation regardless of clinical stability.
7. Subject has a known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies).
8. Subject has known active hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid [qualitative] is detected).
9. Subject has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic therapy (eg, thyroid hormone or insulin)
10. Subject has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of study treatment.
11. Subject has not recovered (ie, to Grade ≤ 1 or to baseline) from cytotoxic therapy-induced AEs. Note: Subjects with Grade ≤ 2 neuropathy, Grade ≤ 2 alopecia, or Grade ≤ 2 fatigue are an exception to this criterion and may qualify for the study.
12. Subject has not recovered adequately from AEs or complications from any major surgery prior to starting therapy.
13. Subject has a known hypersensitivity to carboplatin, paclitaxel, or dostarlimab components or excipients.
14. Subject is currently participating and receiving study treatment or has participated in a study of an investigational agent and received study treatment or used an investigational device within 4 weeks of the first dose of treatment.
15. Subject is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active infection requiring systemic therapy. Specific examples include, but are not limited to, active, noninfectious pneumonitis; uncontrolled ventricular arrhythmia; recent (within 90 days) myocardial infarction; uncontrolled major seizure disorder; unstable spinal cord compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study (including obtaining informed consent).
16. Subject is pregnant or breastfeeding or is expecting to conceive children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study treatment.

E.5 End points

E.5.1

Primary end point(s)

PFS, which is defined as the time from the date of randomization to the earliest date of Investigator assessment of PD or death by any cause in the absence of PD, whichever occurs first.

E.5.1.1

Timepoint(s) of evaluation of this end point

Date of first documentation of progression or death by any cause in the absence of progression, whichever occurs first.

E.5.2

Secondary end point(s)

1. PFS, defined as the time from randomization to the earliest date of assessment of PD per RECIST v.1.1 based on BICR assessment or death by any cause in the absence of PD per RECIST v.1.1, whichever occurs first.
2. OS, defined as the time from randomization to the date of death by any cause.
5. DCR, defined as the proportion of subjects who have achieved a BOR of CR, PR, or stable disease (SD) per RECIST v.1.1 based on Investigator assessment.

3. ORR, defined as the proportion of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR).
4. DOR, defined as the time from the first documentation of CR or PR until the time of the first documentation of subsequent PD per RECIST v.1.1 based on Investigator assessment or death by any cause in the absence of PD per RECIST v.1.1, whichever occurs first.
6. PRO assessment of treatment using EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-EN24.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Date of first documentation of progression or death by any cause in the absence of progression, whichever occurs first.
2. Date of death.
3. End of study.
4. First documentation of PD or death by any cause in the absence of progression from the first documentation of CR or PR.
5. End of study.
6. Study visits, including follow up.

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

Yes

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

E.6.11

Pharmacogenomic

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belarus

Belgium

Canada

Czech Republic

Denmark

Finland

Germany

Greece

Hungary

Israel

Italy

Netherlands

Norway

Poland

Sweden

Turkey

Ukraine

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

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

LVLS

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1