Study of Pembrolizumab Combined With Ataluren In Patients With Metastatic pMMR and dMMR Colorectal Adenocarcinomas or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 47
- Locations
- 1
- Primary Endpoint
- Incidence of treatment-Emergent Adverse Event and the determination of the maximum tolerable dose of Ataluren.
Study Overview
Brief Summary
Single Center, open label, Phase I-II trial designed to test the safety and efficacy of the combination of Ataluren and Pembrolizumab for the treatment of metastatic mismatch repair deficient and proficient colorectal adenocarcinoma and metastatic mismatch repair deficient endometrial carcinoma.
Detailed Description
In controlling tumor outgrowth an intact immune surveillance is very important. PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress this immune control.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody designed to directly block the interaction between PD-1 and its ligands and is registered for the treatment of advanced (unresectable or metastatic) melanoma of locally advanced or metastatic NSCLC in adults. In an earlier study it's effect has been shown in mismatch repair deficient tumors.
Ataluren is designed to allow the protein making apparatus (the ribosome) in cells to skip over a premature stop codon (PTC), allowing the cells to translate the sequence downstream of a premature termination codon (PTC) in mRNA transcripts. This may result in the translation of additional out-of-frame code, which is available in abundance in dMMR tumors. We argue that this may result in new target peptides for the immune-system to recognize cancer cells.
The investigators hypothesize that the formation of these peptides by Ataluren can enhance the effect of Pembrolizumab anti-PD1 therapy.
Therefore the investigators designed a Single Center, open label, Phase I-II trial designed to test the safety and efficacy of the combination of Ataluren and Pembrolizumab for the treatment of metastatic mismatch repair deficient and proficient colorectal adenocarcinoma and metastatic mismatch repair deficient endometrial carcinoma.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Phase I dMMR and pMMR
2-4 groups of 3 patients treatment with 200mg i.v. Pembrolizumab q3w and dose escalation of Ataluren in order to determine the Ataluren MTD. These patients can either be pMMR/dMMR CRC and dMMR EC patients.
Intervention: Ataluren + Pembrolizumab (Drug)
Phase II dMMR
Mismatch repair deficient CRC or EC patients treated with 200mg i.v. pembrolizumab q3w and Ataluren at MTD.
Intervention: Ataluren + Pembrolizumab (Drug)
Phase II pMMR
Mismatch repair proficient CRC patients treated with 200mg i.v. pembrolizumab q3w and Ataluren at MTD.
Intervention: Ataluren + Pembrolizumab (Drug)
Outcomes
Primary Outcomes
Incidence of treatment-Emergent Adverse Event and the determination of the maximum tolerable dose of Ataluren.
Time Frame: Initial dose escalation for Ataluren for first 12 pt in groups of 3, which will approximately take 1 year. All adverse events will be further reported at study compeltion: expected to be after 2 years
To characterize toxicities and side effects of Ataluren when combined with pembrolizumab in patients with pMMR CRC, dMMR mCRC and dMMR EC. Recorded on Adverse Events form and ranking adverse event severity according to the NCI Common Terminology Criteria for Adverse Events v3.0
Objective response rate
Time Frame: 30 weeks
Measured by immune-related response criteria
Secondary Outcomes
- Immune-related progression free survival(21 weeks and 30 weeks)
- Overall survival(trough study completion: expected after 2 years.)
- Progression free survival(at 30 weeks)
- Overall response rate(trough study completion: expected after 2 years.)
- Historic case matching(trough study completion: expected after 2 years)
Investigators
Adriaan D. Bins
MD PhD; Principal Investigator; Oncologist
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)