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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out whether the study drug, TSR-042, followed by standard chemoradiotherapy (the chemotherapy drug capecitabine + radiation therapy) and standard surgery is an effective treatment for advanced dMMR solid tumors. The study will also look at the safety of the study drug.

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.

What data supports the effectiveness of the drug dostarlimab (Jemperli) when used with chemoradiation for cancer?

Dostarlimab has shown effectiveness in treating certain types of cancer, like endometrial cancer, by blocking a protein that helps cancer cells hide from the immune system. It has also demonstrated promising results in a trial for rectal cancer, achieving a 100% remission rate, suggesting its potential in combination therapies for other cancers. ^{1 2 3 4 5}

Is dostarlimab (Jemperli) safe for humans?

Dostarlimab has been shown to be generally safe in humans, with studies indicating it was well tolerated in animal models and clinical trials. In a study, only a small percentage of patients developed antibodies against the drug, and this did not affect its safety or effectiveness. ^{1 2 3 6 7}

What makes the drug dostarlimab unique for cancer treatment?

Dostarlimab is unique because it is a PD-1 blocking antibody that enhances the immune system's ability to fight cancer, and it has shown promising results in treating cancers with specific genetic features, like mismatch repair deficiency, leading to its approval for certain advanced cancers. ^{1 2 3 5 7}

Research Team

Andrea Cercek, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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, 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]

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]

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]

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-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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Dostarlimab: First Approval. [2021]

2. United States 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. [2022]

3. United States 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. [2023]

4. United States 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. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Dostarlimab: A Review. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

An Integrated Analysis of Dostarlimab Immunogenicity. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

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