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.
Inclusion Criteria:
- Participant is at least 18 years of age.
- 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:
- a. Part 1: Any histologically or cytologically proven recurrent advanced solid tumor
- b. Part 2A: : Any histologically or cytologically proven recurrent advanced solid
tumor
- 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:
- 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)
- Participants who have progressed on or after platinum doublet therapy
- 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.
- All endometrial cancer histologies are allowed except endometrial sarcoma (including
carcinosarcoma).
- 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
1.1 to Central Radiology prior to the first dose of dostarlimab.
- Presence of at least 1 measurable lesion on Baseline scan will be confirmed by central
radiology review.
- 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.
- 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.
- 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)
- 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)
- Cohort F - Participants with recurrent or advanced dMMR/MSI-H solid tumors or POLE-mut
solid tumors, except endometrial cancers, that have progressed following up to 2 prior
lines of systemic therapy for recurrent or advanced (>=Stage IIIB) disease 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.
- dMMR/MSI-H colorectal cancer (CRC) participants must have progressed after or been
intolerant to treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
Progression following up to 3 prior lines of therapy is allowed.
- Ovarian cancer participants with platinum-resistant disease (i.e., progression
occurred <6 months on or after platinum doublet chemotherapy): receipt of up to 1 line
of systemic therapy after becoming platinum-resistant is allowed.
- Participants must submit 2 scans demonstrating increase in tumor measurement that meet
criteria for PD based on RECIST 1.1 to Central Radiology prior to the first dose of
dostarlimab.
- Tumor MMR/MSI or POLE status: 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 participants
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 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.
- Participants who are considered for the study based on POLE mutation must have the
local results available showing tumor mutation(s) in the exonuclease domain of the
POLE gene (amino acid residues 268-471) to begin screening. Participants must have the
quality of submitted tumor samples checked and cleared by a central IHC laboratory
prior to receiving study treatment.
- 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.
- 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) must be
less than 6 months.
- 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 v1.1 (i.e., hormonal therapy given for increasing Cancer
antigen [CA]-125 levels) is not counted as a separate line of therapy.
- 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).
- Part 2B: Participants must have archival tumor tissue available that is formalin-fixed
and paraffin-embedded.
- 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.
- 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.
- 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.
- 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.
- 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.
- Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of <=
2 for Part 1 and <= 1 for Part 2.
- Participant has an adequate organ function.
Exclusion Criteria
- Participant has received prior therapy with an anti- programmed death receptor 1
(anti-PD-1), anti-PD-1- ligand-1 (anti-PD-L1), or anti-PD-1 ligand-2 (anti-PD- L2)
agent.
- Participant has a known uncontrolled central nervous system (CNS) metastases and/or
carcinomatous meningitis.
- Participant has a known additional malignancy that progressed or required active
treatment within the last 2 years. Exceptions include basal cell carcinoma of the
skin, squamous cell cancer (SqCC) of the skin that has undergone potentially curative
therapy, or in situ cervical cancer.
- Participant 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, non-infectious
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).
- Participant is pregnant or breastfeeding, or expecting to conceive children within the
projected duration of the study, starting with the Screening Visit through 150 days
after the last dose of study treatment.
- Participant has a diagnosis of immunodeficiency or is receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of study treatment.
- Participant has a known history of human immunodeficiency virus (HIV) (HIV 1/2
antibodies).
- Participant has a known active hepatitis B (eg, hepatitis B surface antigen [HBsAg]
reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid (HCV RNA)
(qualitative) is detected).
- Participant has an active autoimmune disease that has required systemic treatment in
the past 2 years (i.e., with use of disease- modifying agents, corticosteroids, or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment. Use of inhaled steroids, local
injection of steroids, and steroid eye drops are allowed.
- Participant has as history of interstitial lung disease.
- Participant has not recovered (i.e., to <= Grade 1 or to Baseline) from radiation- and
chemotherapy-induced AEs or received transfusion of blood products (including
platelets or red blood cells) or administration of colony-stimulating factors
(including granulocyte-colony stimulating factor [G-CSF], granulocyte macrophage
colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 3 weeks prior
to the first dose of study drug.
- Participant has participated in a study of an investigational agent and received study
therapy or used an investigational device within 4 weeks prior to the first dose of
study drug.
- Participant has received prior anti-cancer therapy (chemotherapy, targeted therapies,
radiotherapy, or immunotherapy) within 21 days, or less than 5 times the half-life of
the most recent therapy prior to study Day 1, whichever is shorter.
- Participant has not recovered adequately (<= Grade 1) from AEs and/or complications
from any major surgery prior to starting therapy.
- Participant has received a live vaccine within 14 days of planned start of study
therapy.
- Participant has a known hypersensitivity to dostarlimab components or excipients.
- For Cohort G, participants will not be eligible if they meet the following criteria:
- Participants who experienced disease progression within 3 months (as evidenced by
radiographic progression per RECIST) of first-line platinum therapy.
- Participants with known deleterious or suspicious deleterious mutation in BRCA1 or
BRCA2 genes (local testing permitted).
- Participants has received prior therapy with a poly(adenosine diphosphate-ribose)
polymerase (PARP)-1/PARP-2 inhibitor.
- Participant has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, might interfere with the
participant's participation for the full duration of the study treatment, or is not in
the best interest of the participant to participate.
- Participant is immunocompromised. Participants with splenectomy are allowed.
