Pembrolizumab plus Ataluren for metastatic colorectal or endometrial cancer with mismatch repair changes

Study of Pembrolizumab Combined With Ataluren In Patients With Metastatic pMMR and dMMR Colorectal Adenocarcinomas or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study

This trial will try the combination of pembrolizumab and ataluren in adults with metastatic colorectal cancer (with or without mismatch repair deficiency) or metastatic mismatch-repair-deficient endometrial cancer to see if the treatment is safe and helps shrink tumors.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 47 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Academic / other)
• Drugs / interventions: pembrolizumab, chemotherapy, radiation
• Locations: 1 site (Amsterdam, North Holland)
• Trial ID: NCT04014530 on ClinicalTrials.gov

What this trial studies

This is a single-center, open-label Phase I–II trial testing pembrolizumab (an anti–PD-1 antibody) given with ataluren, a drug designed to allow read-through of premature stop codons, which may generate new tumor peptides. Investigators hypothesize that ataluren could increase neoantigen production—especially in mismatch repair–deficient tumors—and thereby enhance pembrolizumab’s immune-mediated tumor control. The study enrolls adults with measurable metastatic colorectal adenocarcinoma (dMMR or pMMR) or metastatic dMMR endometrial carcinoma who have received prior therapy, requires fresh pre-treatment biopsies, and will monitor safety, response, and biomarkers. Early phase dosing/safety (Phase I) will be followed by a Phase II expansion to measure anti-tumor activity.

Who should consider this trial

Good fit: Adults with measurable metastatic colorectal cancer (dMMR or pMMR) or metastatic dMMR endometrial cancer who have had at least one prior systemic therapy (or declined palliative chemotherapy), have adequate organ function, and can provide a pre-treatment tumor biopsy are ideal candidates.

Not a fit: Patients with poor organ or marrow function, very limited life expectancy, inability to undergo biopsy, or cancers unlikely to generate new immunogenic peptides may be unlikely to benefit.

Why it matters

Potential benefit: If successful, the combination could increase tumor responses and prolong disease control by creating new immune targets and boosting PD‑1 blockade activity.

How similar studies have performed: PD‑1 inhibitors like pembrolizumab have shown clear activity in mismatch repair–deficient tumors, but using ataluren to induce novel tumor peptides is a novel approach that has not been proven in cancer patients.

Eligibility criteria

In order to be eligible for participation in this trial, the subject must:

* Have at least one lesion with measurable disease as defined by 10mm in longest diameter for a soft tissue lesions or 15mm in short axis for a lymph node by RECIST 1.1 and irRC criteria for response assessment.
* Have received at least 1 prior cancer therapy regimen for metastatic CRC, or have refused palliative chemotherapy. In the latter case this should have been documented.
* Have a life expectancy of greater than 3 months.
* Have normal organ and marrow function as defined in protocol
* Be willing and able to provide written informed consent/assent for the trial.
* Be at least 18 years of age on day of signing informed consent.
* Be willing to provide tissue from a newly obtained pre-treatment core or excisional biopsy of a metastatic tumor lesion and the primary tumor lesion (when in place). Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible by colonoscopy or CT-guided approaches or due to safety concerns) may submit an archived specimen only upon agreement from the Sponsor.
* Be willing to provide tissue post-treatment of a core or excisional biopsy of a metastatic tumor lesion (when still in place) or of the primary tumor (when in place).
* Have a performance status of 0 or 1 on the ECOG Performance Scale.
* Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
* Male subjects of childbearing potential (Section 4.7.2) must agree to use an adequate method of contraception as outlined in Section 4.7.2- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Subject must be excluded from participating in the trial if the subject:

* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 1 week prior to trial treatment.
* Has a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, or anti-CTLA-4 antibodies.
* Has received growth factors including, but not limited to, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin, etc. within 2 weeks of study drug administration. Use of such agents while on study is also prohibited. Prior use of growth factors should be documented in the patient's medical history.
* Has an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Has a history of any autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[e.g., Wegener's Granulomatosis\]); CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis, multiple sclerosis). Patients with thyroid disease will be allowed. Autoimmune diagnoses not listed here must be approved by the protocol chair.
* 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 trial treatment.
* Has a known history of active TB (Bacillus Tuberculosis)
* Hypersensitivity to pembrolizumab or ataluren or any of their excipients.
* Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
* Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
* Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
* Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Has known history of, or any evidence of active, non-infectious pneumonitis.
* Has an active infection requiring systemic therapy.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
* Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
* Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
* Has received a live vaccine within 30 days of planned start of study therapy.
* Has received amino glucoside antibiotics within 3 days of planned start of study therapy

Where this trial is running

Amsterdam, North Holland

• Amsterdam UMC, AMC — Amsterdam, North Holland, Netherlands (Recruiting)

Study contacts

• Principal investigator: Adriaan D Bins, MD PhD — Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Study coordinator: Adriaan D Bins, MD PhD

Conditions Colorectal Cancer; Endometrium Cancer; Mismatch repair; Anti PD1; Immunotherapy; Metastatic disease