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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.

Mismatch repair deficient CRC or EC patients treated with 200mg i.v. pembrolizumab q3w and Ataluren at MTD.

Mismatch repair proficient CRC patients treated with 200mg i.v. pembrolizumab q3w and Ataluren at MTD.

Ataluren and Pembrolizumab combination therapy

Ataluren + Pembrolizumab

Adriaan D Bins, MD PhD

Ide T Spaanderman, MD

Adriaan D. Bins, MD PhD

Punt, Prof.

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.

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.

In the phase-1 part of the study 2-4 groups of 3 patients each are treated with pembrolizumab 200mg i.v. q3w but with increasing ataluren doses (i.e. group1 25%, group2 50% and group3 100% of 10-10-20mg/kg). These can be either pMMR mCRC, dMMR mCRC or dMMR EC patients. The reported toxicity in phase-1 will be used to define the maximum tolerated dose (MTD) of the combination, that will determine the ataluren dose in phase-2.

In the phase-2 part of the study a dMMR group (cohort A, 20 patients either CRC of EC) and a pMMR group (cohort B, 15 CRC patients) will be treated with pembrolizumab 200mg i.v. q3w combined with ataluren t.i.d. at the MTD defined in phase-1.

Historic case-matched controls from the MK-3475-016 study (ClinicalTrials.gov Identifier NCT01876511) and the MK-3475-177 study (ClnicalTrials.gov Identifier NCT02563002).

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

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

mRNA and DNA sequencing measurements from normal blood, tumor, metastatic and polyp tissue: outcome measure will be mutations in DNA and RNA.

Biomarker measurements from normal blood: CEA and neoantigens (peptides)

Elispot assays from PBMCs derived from patient blood samples to check for IFN-gamma production after peptide stimulation

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

Measured by immune-related response criteria

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pembrolizumab With Ataluren in Patients With Metastatic pMMR and dMMR Colorectal Carcinoma or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study	NCT04014530	Colorectal Canc... Endometrium Can...	Ataluren + Pemb...	18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Pembrolizumab With Ataluren in Patients With Metastatic pMMR and dMMR Colorectal Carcinoma or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study	NCT04014530	Colorectal Canc... Endometrium Can...	Ataluren + Pemb...	18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Pembrolizumab With Ataluren in Patients With Metastatic pMMR and dMMR Colorectal Carcinoma or Metastatic dMMR Endometrial Carcinoma: the ATAPEMBRO Study	NCT04014530	Colorectal Canc... Endometrium Can...	Ataluren + Pemb...	18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Spots Global Cancer Trial Database for ataluren + pembrolizumab