Phase 1
Completed N=52
Study of TSR-033 With an Anti-programmed Cell Death-1 Receptor (PD-1) in Participants With Advanced Solid Tumors
Source: ClinicalTrials.gov NCT03250832 ↗Enrolled (actual)
52
Serious AEs
31.9%
Results posted
Feb 2024
Primary outcomePrimary: Part 1A: Number of Participants Experiencing Dose Limiting Toxicity (DLT) — 0; 1; 0; 0 Participants
Summary
This is a multicenter, open-label, first-in-human Phase 1 study evaluating the anti-lymphocyte activation gene-3 (LAG-3) antibody TSR-033 alone, in combination with the anti-PD-1 antibody dostarlimab, and in combination with dostarlimab, modified folinic acid (FOL)/leucovorin, 5-fluorouracil and oxaliplatin (OX) (mFOLFOX6) or FOL/leucovorin, 5-fluorouracil and irinotecan (IRI) (FOLFIRI), and bevacizumab in participants with advanced solid tumors in a broad range of solid tumors. Participants with disease types selected for evaluation in this study are expected to derive clinical benefit with addition of an anti-PD-1. The study will be conducted in two parts with Part 1 consisting of dose escalation to determine the recommended phase 2 dose (RP2D) of TSR-033 as a single agent (Part 1a) and in combination with dostarlimab (Part 1c). RP2D decisions will be based on the occurrence of dose-limiting toxicities (DLTs), pharmacokinetics (PK), as well as pharmacodynamics (PDy) data. Part 2A of the study will investigate the anti-tumor activity of TSR-033 and dostarlimab in combination in participants with advanced or metastatic microsatellite stable colorectal cancer (MSS-CRC). Part 2B of the study will investigate the safety and anti-tumor activity of TSR-033 and dostarlimab in combination with chemotherapy (Cohort B1: mFOLFOX6 and Cohort B2: FOLFIRI) and bevacizumab in participants with advanced or metastatic MSS-CRC.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part 1A: Number of Participants Experiencing Dose Limiting Toxicity (DLT) |
0; 1; 0; 0 | — |
| PRIMARY Part 1C: Number of Participants Experiencing DLT |
0; 0; 0 | — |
| PRIMARY Part 2B: Number of Participants Experiencing DLT |
0; 0 | — |
| PRIMARY Part 1: Number of Participants With Serious Adverse Events (SAEs), Treatment-emergent AEs (TEAEs)and Immune-related AEs (irAEs) |
1; 5; 2; 1; 1; 3 | — |
| PRIMARY Part 2B: Number of Participants With SAEs, TEAEs and irAEs |
4; 7; 4; 21; 3; 11 | — |
| PRIMARY Part 1: Number of Participants With Grade Shift From Baseline in Hematology Parameters |
0; 0; 0; 1; 0; 1 | — |
| PRIMARY Part 2B: Number of Participants With Grade Shift From Baseline in Hematology Parameters |
0; 2; 1; 2; 1; 0 | — |
| PRIMARY Part 1: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Part 2B: Number of Participants With Grade Shift From Baseline in Clinical Chemistry Parameters |
0; 2; 0; 2 | — |
| PRIMARY Part 1: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Creatinine, Bilirubin, Alkaline Phosphatase |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Part 2B: Number of Participants With Grade 3 and 4 Toxicities in Clinical Chemistry Parameters - Alanine Aminotransferase, Aspartate Aminotransferase, Creatinine, Bilirubin |
1; 0; 1; 1; 1; 2 | — |
| PRIMARY Part 1: Number of Participants With Post Baseline Abnormal Electrocardiogram (ECG) Results |
1; 2; 1; 0; 0; 0 | — |
| PRIMARY Part 2B: Number of Participants With Post Baseline Abnormal ECG Results |
1; 2; 1; 5; 1; 2 | — |
| PRIMARY Part 2A: Objective Response Rate (ORR) |
2.9 | — |
| SECONDARY Part 1ab: Area Under the Concentration-time Curve From Time Zero to Last Measurable Concentration (AUC [0-last]) of TSR-033 |
606.4256; 2601.731; 8176.4963; 23763.7645 | — |
| SECONDARY Part 1c: AUC (0-last) of TSR-033 and Dostarlimab |
2615.4485; 9317.8306; 30750.7484; 24303.8328; 25301.7468; 26326.0589 | — |
| SECONDARY Part 1ab: AUC Extrapolated From Time Zero to Infinity (AUC [0-inf]) of TSR-033 |
858.3739; 2783.4404; 12517.0356; 44300.8914 | — |
| SECONDARY Part 1c: AUC (0-inf) of TSR-033 and Dostarlimab |
3201.6715; 12336.2784; 52144.2561; 30692.5087; 34298.0046; 37944.78 | — |
| SECONDARY Part 1ab: AUC Over a Dosing Interval at Steady State (AUCtau) of TSR-033 |
816.9529; 3171.9548; 9432.5708; 27125.0835 | — |
| SECONDARY Part 1c: AUCtau of TSR-033 and Dostarlimab |
2929.7274; 11351.945; 39920.9217; 29866.3126; 32396.6385; 32702.9638 | — |
| SECONDARY Part 1ab: Maximum Concentration (Cmax) of TSR-033 |
7.489; 22.81; 74.13; 217.1 | — |
| SECONDARY Part 1c: Cmax of TSR-033 and Dostarlimab |
23.04; 73.5; 312.8; 171.6; 163; 170.8 | — |
| SECONDARY Part 1ab: Clearance (CL) of TSR-033 |
0.0233; 0.0287; 0.0192; 0.0163 | — |
| SECONDARY Part 1c: CL of TSR-033 and Dostarlimab |
0.025; 0.0195; 0.0138; 0.0163; 0.0146; 0.0132 | — |
| SECONDARY Part 1ab: Volume of Distribution at Steady State (Vss) of TSR-033 |
3.4821; 5.0563; 4.8329; 5.2564 | — |
| SECONDARY Part 1c: Vss of TSR-033 and Dostarlimab |
4.8162; 5.3978; 4.3845; 4.4915; 4.6431; 4.3544 | — |
| SECONDARY Part 1ab: Terminal Half-life (t1/2) of TSR-033 |
119.7937; 240.5387; 198.8801; 214.2533 | — |
| SECONDARY Part 1c: t1/2 of TSR-033 and Dostarlimab |
140.4589; 241.0348; 226.5019; 259.3884; 318.7548; 286.253 | — |
| SECONDARY Part 1ab: Number of Participants With Anti-TSR-033 Antibodies |
0; 0; 0; 0 | — |
| SECONDARY Part 1c: Number of Participants With Anti-TSR-033 Antibodies |
1; 0; 0 | — |
| SECONDARY Part 2A: Number of Participants With Anti-TSR-033 Antibodies |
— | — |
| SECONDARY Part 2B: Number of Participants With Anti-TSR-033 Antibodies |
0; 0 | — |
| SECONDARY Part 1ab: Objective Response Rate (ORR) |
0; 0; 0; 0 | — |
| SECONDARY Part 1c: Objective Response Rate (ORR) |
0; 0; 0 | — |
| SECONDARY Part 2B: Objective Response Rate (ORR) |
0; 20 | — |
| SECONDARY Part 2A: Duration of Response (DOR) |
23.3 | — |
| SECONDARY Part 2B: Duration of Response (DOR) |
14.1 | — |
| SECONDARY Part 2A: Disease Control Rate (DCR) |
8.8 | — |
| SECONDARY Part 2B: Disease Control Rate (DCR) |
50; 80 | — |
Eligibility Criteria
Inclusion Criteria for participants in Part 1:
- The participant is >=18 years of age.
- The participant has any histologically or cytologically confirmed advanced (unresectable) or metastatic solid tumor and has PD after treatment with available therapies that are known to confer clinical benefit or who are intolerant to treatment.
- The participant must have an archival tumor tissue sample that is formalin-fixed and paraffin-embedded (FFPE) (blocks preferred over slides) and requested and confirmed available from offsite locations prior to dosing. The quality and quantity of the sample must be confirmed sufficient as per the Study Laboratory Manual. Participants who do not have archival tissue must agree to a new biopsy to obtain fresh tumor tissue prior to dosing.
- Part 1b (PK/PDy cohort): The participant must have lesions amenable for biopsy and agree to undergo biopsies for fresh tumor tissue prior to treatment, approximately 4 to 6 weeks after treatment, and, whenever possible, at the time of PD and /or end of treatment (EOT). Serial biopsies are optional for participants in Part 1a and 1c.
- Female participants must have a negative serum or urine pregnancy test within 72 hours prior to the date of the first dose of study medication if of childbearing potential or be of non-childbearing potential. Non-childbearing potential is defined as:
- Participants >=45 years of age and has not had menses for >1 year.
- Amenorrheic for =1500 per microliter (/μL).
- Platelets >=100,000/μL.
- Hemoglobin (Hb) >=9 grams per deciliter (g/dL) or >=5.6 millimoles per liter (mmol/L).
- Serum creatinine =50 milliliters per minute (mL/min) using Cockcroft-Gault equation for participants with creatinine levels >1.5 × institutional ULN
- Total bilirubin = 18 years of age.
- The participant has any histologically or cytologically confirmed CRC that is metastatic or not amenable to potentially curative resection (advanced), in the opinion of the Investigator.
- The participant has a primary and/or metastatic tumor(s) that is known to be MSS, as determined locally.
- The participant must have lesions amenable for biopsy and agree to undergo biopsies for fresh tumor tissue prior to treatment, approximately 4 to 6 weeks after, and, whenever possible, at EOT and/or the time of PD. If the participant has had a biopsy prior to entering the 28-day screening period, and within approximately 12 weeks of study treatment, that biopsy sample may be accepted as the Baseline fresh biopsy. Additionally, submission of sufficient high-quality archival tumor tissue is recommended, if available, to enable a longitudinal analysis of tumor biomarkers.
- The participant has measurable disease by RECIST v1.1.
- The participant has resolution to Grade =45 years of age and has not had menses for >1 year.
- Amenorrheic for =1500/μL.
- Platelets >=100,000/μL.
- Hb >=9 g/dL or >=5.6 mmol/L.
- Serum creatinine =50 mL/min using Cockcroft-Gault equation for participants with creatinine levels >1.5 × institutional ULN
- Total bilirubin =2+, a 24-hour urine sample must be collected and must demonstrate =3.0 g/dL.
Inclusion Criteria for participants in Part 2A:
- The participant must have had at least 2, but no more than 3, prior lines of therapy in the advanced or metastatic setting. Adjuvant chemotherapy with radiographic progression >12 months after the last dose will not be considered a line of therapy.
- The participant has progressed on standard therapies or withdrawn from standard treatment due to unacceptable toxicity. Previous standard treatment must include all of the following:
- Fluoropyrimidine.
- Oxaliplatin: Participants treated with oxaliplatin in adjuvant setting should have progressed after 12 months of completion of adjuvant therapy or they must have been treated with oxaliplatin for metastatic disease.
- Irinotecan.
- Participants whose disease is known to be RAS-wild-type must have been treated with cetuximab, panitumumab, or other epidermal growth fact
Data sourced from ClinicalTrials.gov (NCT03250832). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.