Summary

This is a multi-center, open-label, first-in-human Phase 1 study evaluating the
anti-programmed death receptor 1 (anti-PD-1) antibody dostarlimab (also known as TSR-042)
n participants with advanced solid tumors who have limited available treatment options.
The study will be conducted in 2 parts with Part 1 consisting of safety evaluation,
pharmacokinetics (PK), and pharmacodynamics (PDy) of escalating doses of dostarlimab.
Dose escalation will be based on ascending weight-based dose levels (DLs) of dostarlimab
and will continue until the maximum tolerated dose (MTD) is reached or may be stopped at
any dose level up to the highest dose of 20 milligrams per kilograms (mg/kg) based on
emerging safety and PK/PDy data. Part 2 will be conducted in two subparts, Part 2A
(fixed-dose safety evaluation cohorts) and Part 2B (expansion cohorts). Part 2A of the
study will evaluate the safety and tolerability of dostarlimab at fixed doses of 500 mg
administered every 3 weeks (Q3W) and 1000 mg administered every 6 weeks (Q6W). Part 2B of
the study will examine the safety and clinical activity of dostarlimab in cohorts of
participants with specific types of advanced solid tumors.

Eligibility

1. Participant is at least 18 years of age.
2. Participant has proven recurrent or advanced solid tumor and has disease progression after treatment with available anti cancer therapies, or is intolerant to treatment that meets the following requirements for the part of the study they will participate in:
3. a. Part 1: Any histologically or cytologically proven recurrent advanced solid tumor
4. b. Part 2A: : Any histologically or cytologically proven recurrent advanced solid tumor
5. c. Part 2B: Histologically of cytologically proven recurrent or advanced solid tumor with measurable lesion(s) per RECIST version 1.1 and meets one of the following disease types:
6. The criteria below should be met for participant participating in: Cohort A1 (dMMR/MSI-H endometrial cancer) and Cohort A2 (MMR-proficient/MSS endometrial cancer)
7. Participants who have progressed on or after platinum doublet therapy
8. Participants have received no more than 2 lines of anti-cancer therapy for recurrent or advanced (>=Stage IIIB) disease. Prior treatment with hormone therapies is acceptable and does not count towards the number of anti-cancer therapies noted in the criterion above for this cohort.
9. All endometrial cancer histologies are allowed except endometrial sarcoma (including carcinosarcoma).
10. Participants must submit 2 scans demonstrating increase in tumor measurement that meet criteria for PD on or after the latest systemic anti-cancer therapy based on RECIST Version 1.1 to Central Radiology prior to the first dose of dostarlimab.
11. Presence of at least 1 measurable lesion on Baseline scan will be confirmed by central radiology review.
12. Status of tumor MMR/MSI: Participants can be screened based on local MMR/MSI testing results using immunohistochemistry (IHC), polymerase chain reaction (PCR), or next generation sequencing (NGS) performed in a certified local laboratory, but participant eligibility needs to be determined by MMR IHC results. For participant with available local MMR IHC results for the respective cohort(s), tumor samples have to be submitted to a central IHC laboratory and its quality has to be checked and cleared prior to Cycle 1 Day 1 (C1D1). For participants without available local MMR IHC test results (participants with local PCR or NGS test results), central IHC results have to confirm eligibility prior to proceeding with other screening procedures. After the central IHC test is completed, remaining tumor tissue may be tested for further exploratory biomarkers or may be sent to a central NGS laboratory for further testing.
13. Cohort E - Participants with NSCLC who progressed after at least 1 prior platinum-based systemic chemotherapy regimen for recurrent or advanced disease. Chemotherapy regimen in the adjuvant or neoadjuvant setting following surgery and/or radiation is acceptable if recurrent or advanced disease develops within 6 months from completion of therapy.
14. Participants with a known epidermal growth factor receptor (EGFR) mutation must have received a chemotherapy regimen and an EGFR tyrosine-kinase inhibitor (TKI) (e.g., erlotinib, gefitinib, afatinib, or experimental)
15. Participants with a known anaplastic lymphoma kinase (ALK) translocation must have received a chemotherapy regimen and an ALK inhibitor (e.g., crizotinib, ceritinib or experimental)
16. Cohort F - Participants with recurrent or advanced dMMR/MSI-H solid tumors except endometrial cancers and gastrointestinal cancers, who have received prior systemic therapy and who have no alternative treatment options. Prior treatment with hormone therapies alone given for recurrent or advanced disease is acceptable and does not count towards the number of anti-cancer therapies.
17. Measurable lesion by RECIST 1.1 Radiology on baseline scan will be confirmed by central radiology review prior to first dose of dostarlimab. Patients with primary CNS tumor should provide brain MRI at baseline.
18. a. Presence of deficient mismatch repair (dMMR) and/or microsatellite instability (MSI-H) in the tumor defined by either:
19. b. deficient DNA mismatch repair (dMMR); MMR status must be assessed by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicates dMMR; dMMR may be determined either locally or by the central reference lab; OR
20. c. Microsatelillite instability (MSI-H); MSI-H as determined by polymerase chain reaction (PCR) or by tissue Next generation sequencing (NGS); MSI-H may be determined locally
21. Cohort G: Participants must have recurrent high-grade serous, endometrioid, or clear cell ovarian, fallopian tube, or primary peritoneal cancer. Participants must have presence of at least 1 measurable lesion on Baseline scan that will be confirmed by central radiology review.
22. Participants must be considered resistant to the last administered platinum therapy, that is, the time from the last administered platinum dose until the initial documented progression (as evidenced by radiographic progression per RECIST version 1.1) must be less than 6 months.
23. Participants must have completed at least 1 but no more than 3 prior lines of therapy for advanced or metastatic ovarian cancer. Neoadjuvant, adjuvant, and the combination of both will be considered as 1 line of therapy. Treatment with single-agent bevacizumab given as maintenance is not counted as a separate line of therapy. If a therapeutic regimen is modified or changed for a reason other than lack of response or PD (such as allergic reaction, toxicity, or drug availability), this is not counted as a separate line of therapy. The use of single-agent hormonal therapy given for reasons other than PD per RECIST version v1.1 (i.e., hormonal therapy given for increasing Cancer antigen [CA]-125 levels) is not counted as a separate line of therapy.
24. Participants must have been previously treated with platinum-based regimen, taxane agent(s), and bevacizumab (bevacizumab could be used as a single agent or in combination with another agent, in frontline therapy, as maintenance, or for treatment of recurrent disease).
25. Part 2B: Participants must have archival tumor tissue available that is formalin-fixed and paraffin-embedded (FFPE).
26. For participants who do not have archival tissue, a new biopsy must be performed to obtain a tissue sample prior to study treatment initiation. For participants without available archival tissue, the biopsy should be taken from the tumor lesions (either primary or metastatic) that have easy accessibility and low biopsy-associated risks and will exclude biopsies of the liver, brain, lung/mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach or bowel.
27. For Cohort F an FFPE tissue sample must be submitted to the central laboratory for testing. For patients with available local MMR/MSI-H results, tumor samples have to be submitted to a central laboratory and its quality has to be checked and cleared prior to C1D1
28. For Cohort G, participant must provide formalin fixed paraffin embedded (FFPE) tumor tissue block(s) with sufficient tumor content (as confirmed by the Sponsor's designated central laboratory) during screening to enable, for example, measures of homologous recombination pathway defects and PD-L1 status. The use of slides created from paraffin-embedded tissue as opposed to FFPE blocks must be approved by the Sponsor.
29. Female participants must have a negative serum pregnancy test within 72 hours prior to the date of the first dose of study medication: unless they are of non-child bearing potential.
30. Non child bearing potential is defined as: >= 45 years of age and has not had menses for > 1 year; Amenorrheic for < 2 years without a hysterectomy and oophorectomy and have a follicle- stimulating hormone (FSH) value in the postmenopausal range upon pre-study (screening) evaluation. Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) scan. Tubal ligation must be confirmed with medical records of the actual procedure.
31. Female participants of childbearing potential must agree to use 1 highly effective form of contraception with their partner starting with the screening visit through 150 days after the last dose of study therapy.
32. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of <= 2 for Part 1 and <= 1 for Part 2.
33. Participant has an adequate organ function.