PD-1 Blockade + Chemoradiation for Cancer

Recruiting at 11 trial locations

Overseen By Andrea Cercek, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Immunosuppressants, Steroids, Anticancer, others

Disqualifiers: Metastatic disease, Autoimmune, Infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a new drug, TSR-042 (also known as Dostarlimab or Jemperli, a PD-1 blockade therapy), combined with standard treatments like chemotherapy and radiation, can effectively treat certain advanced solid tumors with a unique genetic feature (dMMR or MSI-H). The study aims to determine if this combination can shrink tumors and improve patient outcomes. It also evaluates the safety of TSR-042. Suitable participants have advanced solid tumors that haven't spread and are typically treated with chemotherapy and radiation. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, contributing to advancements in cancer therapy.

Do I need to stop taking my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot take other experimental therapies or systemic steroid therapy at non-physiologic doses within 7 days prior to the trial. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that TSR-042, also known as dostarlimab, is safe and well-tolerated. Dostarlimab aids the immune system in fighting cancer by blocking a specific pathway called PD-1. Previous studies have found that its side effects are generally mild and can usually be managed with medical care.

In one study, dostarlimab effectively reduced tumor size for a significant time. The study also found that the side effects were similar to those expected from other drugs targeting the PD-1 pathway. So far, patients have handled dostarlimab well without major issues.

Overall, evidence suggests that dostarlimab is generally safe for patients, although, like any treatment, it may have some side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for cancer?

Researchers are excited about TSR-042, a PD-1 blockade, because it offers a new way to tackle solid tumors, particularly those with high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR). Unlike standard chemotherapy, which targets rapidly dividing cells indiscriminately, TSR-042 specifically targets the PD-1 pathway, a key player in helping cancer cells evade the immune system. This targeted action could lead to fewer side effects and more effective tumor suppression. Additionally, the trial is exploring the potential for non-operative management if a complete clinical response is achieved, which could mean less invasive treatment options for patients.

What evidence suggests that this treatment might be an effective treatment for advanced dMMR solid tumors?

Research has shown that TSR-042, also known as dostarlimab, holds promise for treating advanced solid tumors with a specific genetic issue called dMMR (deficient mismatch repair). One study found that all patients treated with dostarlimab experienced a complete clinical response, meaning their tumors either shrank significantly or disappeared. In this trial, participants in Cohort 1 will receive up to 6 months of PD-1 blockade with TSR-042, followed by radiological and surgical restaging of the tumor. If a complete clinical response is not reached, participants will proceed with standard chemoradiation. Studies have found that treatments like TSR-042, which help the immune system attack cancer, can be very effective as an initial treatment for these tumors. This suggests that TSR-042 could be a powerful option against certain advanced cancers when used before traditional treatments like chemotherapy, radiation, and surgery. ^{1 6 7 8 9}

Who Is on the Research Team?

Andrea Cercek, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors that lack a certain DNA repair mechanism (dMMR). Participants must be willing to use effective contraception, have no distant metastases, measurable disease, and adequate organ function. Excluded are those with prior treatments for the tumor, active infections or autoimmune diseases, recent major surgeries or vaccines, and known HIV or hepatitis.

Inclusion Criteria

Nonchildbearing potential is defined as follows (by other than medical reasons):

Radiologically measurable or clinically evaluable disease

My liver is functioning properly.

Exclusion Criteria

Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected)

I am currently on medication for an infection.

My colorectal cancer is causing symptoms like blockage in my bowel.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

PD-1 Blockade Treatment

Participants receive up to 6 months (9, 21-day cycles) of PD-1 blockade

6 months

Chemoradiotherapy

Participants receive standard chemoradiotherapy with capecitabine and radiation therapy

Varies

Surgical Assessment

Participants are assessed for surgical intervention based on response to prior treatments

Varies

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• TSR-042

Trial Overview The study tests TSR-042 (Dostarlimab) followed by standard chemoradiotherapy (capecitabine + IMRT) and surgery in treating dMMR solid tumors. It aims to evaluate the effectiveness of this combination therapy as well as the safety profile of TSR-042.

How Is the Trial Designed?

Group I: Cohort 2 Experimental Treatment 1 Intervention

The plan is to enroll six patients with MSI, regardless of their primary cancer diagnosis. This cohort will serve to generate hypothesis and initial data to plan a larger study. All analyses from this cohort will be exploratory

Group II: Cohort 1 Experimental Treatment 3 Interventions

Patients with clinical Stage II or Stage III MRI-staged, MSI-H or dMMR, solid tumors will receive up to 6 months (9, 21-day cycles) of PD-1 blockade followed by radiological and surgical restaging of the tumor. If subject exhibits complete clinical response, non-operative management will be followed. If a complete clinical response is not reached after 6 months of PD-1 blockade, the participant will proceed with standard chemoradiation. After completing chemoradiation participant will be assessed for response if complete CR is not obtained then the participant will proceed with disease specific surgical resection or standard of care therapy.

TSR-042 is already approved in United States, European Union for the following indications:

Approved in United States as Jemperli for:

• Endometrial cancer (dMMR/MSI-H)
• Primary advanced or recurrent endometrial cancer

Approved in European Union as Jemperli for:

• Endometrial cancer (dMMR/MSI-H)
• Primary advanced or recurrent endometrial cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Tesaro, Inc.

Industry Sponsor

Trials

57

Recruited

10,600+

Published Research Related to This Trial

Dostarlimab-gxly (Jemperli) has received accelerated approval from the FDA for treating adults with mismatch repair deficient recurrent or advanced endometrial cancer and solid tumors, indicating its potential effectiveness in these specific cancer types.

This approval highlights the importance of targeted therapies in oncology, particularly for patients with specific genetic markers that may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Drug for Mismatch Repair Deficient Endometrial Cancer and Solid Tumors. Aschenbrenner, DS.[2023]

Dostarlimab, a humanized anti-PD-1 antibody, has shown significant antitumor activity in humanized mouse models by enhancing T-cell functions and increasing immune cell infiltration, indicating its potential effectiveness in cancer treatment.

In clinical trials, dostarlimab was well tolerated and received FDA approval for treating adult patients with mismatch repair-deficient recurrent or advanced endometrial cancer, demonstrating its safety and efficacy in a specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical characterization of dostarlimab, a therapeutic anti-PD-1 antibody with potent activity to enhance immune function in in vitro cellular assays and in vivo animal models. Kumar, S., Ghosh, S., Sharma, G., et al.[2022]

In a study involving 478 patients, dostarlimab, an anti-PD-1 monoclonal antibody, showed a low incidence of treatment-emergent antidrug antibodies (ADAs) at 2.5%, indicating a favorable safety profile compared to other similar therapies.

Despite the presence of ADAs in a small number of patients, there was no evidence of reduced efficacy or safety for dostarlimab, supporting its use as an effective treatment for various solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Integrated Analysis of Dostarlimab Immunogenicity. Lu, S., Bowsher, RR., Clancy, A., et al.[2022]

Dostarlimab (JEMPERLI) is a PD-1 monoclonal antibody that has received rapid FDA approval for treating adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, showing promising tumor response rates.

A clinical trial (NCT04165772) reported a remarkable 100% remission rate for rectal cancer patients treated with Dostarlimab, highlighting the potential of matching tumor genetics with targeted therapies, and the trial is ongoing for other cancer types like gastric, prostate, and pancreatic cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dostarlimab: A Review. Costa, B., Vale, N.[2022]

Dostarlimab is a monoclonal antibody that targets the PD-1 receptor and has been approved for treating adult patients with mismatch repair deficient recurrent or advanced endometrial cancer based on promising results from the GARNET trial.

The approval of dostarlimab in the EU and USA marks a significant milestone in cancer treatment, highlighting its potential efficacy in targeting specific cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dostarlimab: First Approval. Markham, A.[2021]

Dostarlimab, an anti-PD-1 monoclonal antibody, has been shown to be equipotent to pembrolizumab in suppressing PD-1 activity, with an estimated effective concentration of 1.95 μg/ml based on data from the GARNET trial.

The recommended dosing regimen for dostarlimab is 500 mg every 3 weeks for 4 cycles, followed by 1000 mg every 6 weeks, which supports its use as a potent treatment option for patients with recurrent or advanced mismatch repair-deficient solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative analysis of PD-1 target engagement of dostarlimab and pembrolizumab in advanced solid tumors using ex vivo IL-2 stimulation data. Austin, D., Melhem, M., Gandhi, Y., et al.[2023]

The combination of PD-1 inhibition with chemoradiotherapy for stage III non-small cell lung cancer (NSCLC) was found to be safe and tolerable, with no dose-limiting toxic effects observed in a study of 21 patients over a median follow-up of 16 months.

Patients receiving at least one dose of pembrolizumab showed a promising median progression-free survival (PFS) of 18.7 months, with 69.7% of patients remaining progression-free at 12 months, indicating potential efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial. Jabbour, SK., Berman, AT., Decker, RH., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02715284

NCT02715284 | Study of TSR-042, an Anti-programmed ... Safety, antitumor activity, and pharmacokinetics of dostarlimab, an anti-PD-1, in patients with advanced solid tumors: a dose-escalation phase 1 trial.

2. gsk.com gsk.com/en-gb/media/press-releases/jemperli-dostarlimab-trial-continues-to-show-unprecedented-results/

Jemperli (dostarlimab) trial continues to show ... The trial showed an unprecedented 100% clinical complete response rate (cCR) in 42 patients who completed treatment with dostarlimab.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2201445

PD-1 Blockade in Mismatch Repair–Deficient, Locally ... Immune checkpoint blockade alone has been shown to be highly effective as first-line treatment for patients with mismatch repair–deficient ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04165772

NCT04165772 | Study of Induction PD-1 Blockade in ... The purpose of this study is to find out whether the study drug, TSR-042, followed by standard chemoradiotherapy (the chemotherapy drug capecitabine + ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10623195/

Antitumor Activity and Safety of Dostarlimab Monotherapy in ... The Study of TSR-042, an Anti–PD-1 Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET) Trial is a phase 1, multicenter, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9694305/

Dostarlimab an Inhibitor of PD-1/PD-L1: A New Paradigm ... Dostarlimab (TSR-042), a drug that interferes with the PD-1/PD-L1 pathway, eliminates a crucial inhibitory response of an immune system.

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(20)38452-0/fulltext

Safety, pharmacodynamic, and pharmacokinetic profile of ... Conclusions: TSR-042 is safe and well tolerated, with a safety profile expected for an agent targeting the PD-1 pathway, with evidence of linear PK and ...

8. jitc.bmj.com jitc.bmj.com/content/10/1/e003777

Safety and antitumor activity of dostarlimab in patients with ... Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile.

9. jpccr.eu jpccr.eu/Dostarlimab-as-a-promising-immunotherapy-for-endometrial-cancer-treatment-literature,172403,0,2.html

Dostarlimab as a promising immunotherapy for ... Preliminary safety, efficacy, and PK/PD characterization from GARNET, a phase I clinical trial of the anti-PD-1 monoclonal antibody, TSR-042, in patients with ...