Pembrolizumab With Ataluren in Patients With Metastatic pMMR and dMMR Colorectal Carcinoma or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study

Phase 1

Recruiting

• Conditions: Colorectal Cancer; Endometrium Cancer
• Interventions: Drug: Ataluren + Pembrolizumab

• Registration Number: NCT04014530
• Lead Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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 Timeline

• Study First Submitted: 2019-02-25
• Study First Submitted QC: 2019-07-09
• Study First Posted: 2019-07-10
• Study Start: 2019-08-01
• Status Verified: 2023-01
• Last Update Submitted: 2023-01-31
• Last Update Posted: 2023-02-01
• Primary Completion: 2023-06-01
• Study Completion: 2023-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 47

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase II dMMR	Ataluren + Pembrolizumab	Mismatch repair deficient CRC or EC patients treated with 200mg i.v. pembrolizumab q3w and Ataluren at MTD.
Phase II pMMR	Ataluren + Pembrolizumab	Mismatch repair proficient CRC patients treated with 200mg i.v. pembrolizumab q3w and Ataluren at MTD.
Phase I dMMR and pMMR	Ataluren + Pembrolizumab	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.

Primary Outcome Measures

Name	Time	Method
Incidence of treatment-Emergent Adverse Event and the determination of the maximum tolerable dose of Ataluren.	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	30 weeks	Measured by immune-related response criteria

Secondary Outcome Measures

Name	Time	Method
Immune-related progression free survival	21 weeks and 30 weeks	irPFS
Overall survival	trough study completion: expected after 2 years.	OS
Progression free survival	at 30 weeks	non immune related PFS
Overall response rate	trough study completion: expected after 2 years.	ORR
Historic case matching	trough study completion: expected after 2 years	Historic case-matched controls from the MK-3475-016 study (ClinicalTrials.gov Identifier NCT01876511) and the MK-3475-177 study (ClnicalTrials.gov Identifier NCT02563002). Case-matching based on overall survival and immune-related response rate.

Trial Locations

Locations (1)

Amsterdam UMC, AMC; 🇳🇱 Amsterdam, Noord-Holland, Netherlands