Metastatic coloretal carcinoma and metastatic endometrial carcinoma
Conditions
Interventions
Ataluren and Pembrolizumab
Sponsors
Amsterdam UMC location AMC
Eligibility
Inclusion criteria
Inclusion criteria: • 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.
Exclusion criteria
Exclusion criteria: • 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, granulocytecolony 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 conditio
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Safety and toxicity To assess safety and characterize toxicities of pembrolizumab combined with ataluren in patients with pMMR CRC, dMMR mCRC and dMMR EC. [Time Frame: Initial dose escalation for Ataluren for first 12 pt in groups of 3.] 2. Objective response rate Measured by immunerelated response criteria [Time Frame: 30 weeks] | — |
Secondary
| Measure | Time frame |
|---|---|
| 3. Immune-related progression free survival irPFS [Time Frame: 21 weeks and 30 weeks] 4. Overall survival OS [Time Frame: end of study] 5. Progression free survival non immune related PFS [Time Frame: at 30 weeks] 6. Overall response rate ORR [Time Frame: end of study] 7. Historic case matching Historic case-matched controls from the MK-3475-016 study (ClinicalTrials.gov Identifier NCT01876511) and the MK-3475-177 study (ClnicalTrials.gov Identifier NCT02563002). [Time Frame: end of study] 8. Explorative objectives pre-post treatment tumor/polyp/healthy tissue mRNA/DNA comparisson, tumor burdon and biomarker idendification, Lymphocyte and T-cell activation against neo-antigens [Time Frame: During/after clinical study] | — |
Contacts
Public ContactAdriaan Bins
Amsterdam UMC, location AMC
Outcome results
None listed