Pembrolizumab In Combination With Debio 1143 In Pancreatic and Colorectal Advanced/Metastatic Adenocarcinoma

NCT03871959 | Completed Phase 1 DMC

• 1 other identifier: ET16-023 CATRIPCA
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

Brief Summary

This trial is a Phase I study to be conducted in patients with non-MSI-high advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer (CRC) and is divided in two Parts.

• Dose escalation Part :To determine the Maximum Tolerated Dose (MTD) and the Recommended Dose for Phase 2 (RP2D) of Debio1143 when combined with a fixed dose of Pembrolizumab.
• Extension Part: To evaluate preliminary efficacy data of the proposed combination.

Conditions

Adenocarcinoma of the Pancreas; Adenocarcinoma of the Colon; Adenocarcinoma of the Rectum

Keywords

PD1 Monoclonal Antibody; IAP Antagonist; phase I; MSI

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose

  To determine the Maximum Tolerated Dose of Debio1143 when combined with a fixed dose of Pembrolizumab.

  21 days

• Recommended Dose for Phase 2

  To determine the Recommended Dose for Phase 2 (RP2D) of Debio1143 when combined with a fixed dose of Pembrolizumab.

  21 days

• Extension Part Objective Response Rate

  The Objective Response Rate will be defined as the proportion of patients with complete response or partial response, as per RECIST V1.1.

  12 weeks

Secondary Outcomes (7)

• Duration of response

  Up to 2 years

• Clinical Benefit Rate

  12 weeks

• Tumor-response efficacy 1

  Up to 2 years

• Tumor-response efficacy 2

  Up to 2 years

• Progression-Free Survival

  Up to 2 years

Study Arms (1)

Pembrolizumab + Debio 1143

EXPERIMENTAL

Pembrolizumab : 200 mg, intravenous (IV), to be administered on Day 1 of every 3-week cycle i.e. Q3W. Debio 1143 : 3 escalating dose level (100 mg, 150 mg, 200 mg) administered daily for 14 days over a 21-day cycle period.

Drug: Pembrolizumab; Drug: DEBIO1143

Interventions

Pembrolizumab DRUG

200 mg, intravenous (IV), to be administered on Day 1 of every 3-week cycle i.e. Q3W.

Also known as: Keytruda

Pembrolizumab + Debio 1143

DEBIO1143 DRUG

3 escalating dose level (100 mg, 150 mg, 200 mg) of Debio 1143 administered daily for 14 days over a 21-day cycle period.

Pembrolizumab + Debio 1143

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients aged of at least 18 years on day of signing informed consent.
• Histologically-confirmed diagnosis of Stage III or IV (according to the current version of the American Joint Committee on Cancer (AJCC)) of PDAC or Stage IV CRC.
• Note: pancreatic endocrine tumors are not eligible.
• Previous treatment in the metastatic / advanced stage: PDAC: at least one line of chemotherapy and CRC: at least one line of chemotherapy containing 5-FU, oxaliplatin, irinotecan, plus bevacizumab if patient is eligible, plus anti-EGFR if CRC with RAS wild-type.
• At least one measurable lesion according to RECIST v1.1.
• Presence of at least one tumor lesion with a diameter ≥20 mm, visible by medical imaging and accessible to repeatable percutaneous (needle biopsies 18 gauge or larger) sampling that permit core needle biopsy (ideally 4 cores) without unacceptable risk of a major procedural complication.
• Note: 1. endoscopic biopsies are not allowed. 2. Lymph nodes, lung and RECIST target lesions are not suitable for de novo biopsies.
• \- Availability of a representative formalin-fixed and paraffin-embedded (FFPE) primary and/or metastatic tumor tissue with an associated pathology report.
• Note: Fine needle aspirates, and bone biopsies do not satisfy the requirement for tumor tissue.
• Note : If adequate tissue from distinct timepoints (such as time of initial diagnosis and time of disease recurrence and/or multiple metastatic tumors is available), priority should be given to the tissue most recently collected (ideally subsequent to the most recent systemic therapy).
• ECOG Performance Status (PS) 0 or 1 (See Appendix 1).
• Life expectancy of at least 12 weeks.
• Demonstrate adequate organ function as defined in table below, all screening laboratory tests should be performed within 7 days prior C1D1.
• HEMATOLOGICAL Absolute neutrophil count (ANC) ≥ 1.5 G/L Platelets ≥ 100 G/L Hemoglobin ≥ 9 g/dL (without transfusion within 7 days) RENAL Serum creatinine OR Creatinine clearance according to CKD-EPI ≤ 1.5 × Upper Limit of Normal (ULN) OR ≥ 50 mL/min/1.73m2 HEPATIC Serum total bilirubin ≤ 1.5 × ULN (except for patients with Gilbert disease for whom a total serum bilirubin ≤ 3 x ULN is acceptable). OR Direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 × ULN ASAT and ALAT ≤ 3 × ULN (or ≤ 5 × ULN in case of liver metastasis or hepatic infiltration) COAGULATION INR and Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN Note: This is applicable only for patients not receiving an anticoagulant treatment: patients receiving therapeutic anticoagulation must be on stable dose.
• Able to swallow and retain orally administered medication.

You may not qualify if:

• Patients amenable to therapy with curative intent.
• Patient participating to another clinical trial with a medicinal product.
• Patients with microsatellite instability (MSI)-high or mismatch repair MMR-deficient tumors.
• Patients who have not recovered from adverse events (i.e. \> Grade 1 according to NCI CTCAE v5.0 See Appendix 5) due to prior treatment with anti-cancer agents with exception of Grade 2 neuropathy, any Grade alopecia or lab values presented in criteria I10.
• Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-CTL-A4 and any ICIs or IAP inhibitors.
• Patients who have a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
• Patients with known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to C1D1 and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids (at doses higher than 10 mg/d of methylprednisolone or equivalent) for at least 4 weeks prior C1D1.
• Patients with a history of autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids (at doses higher than 10 mg/d of methylprednisolone or equivalent) or immunosuppressive agents.
• Patients with history of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
• Patients with an evidence of active infection requiring systemic therapy.
• Patients with a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial.
• Patients with a history of uncontrolled or symptomatic, clinically significant cardiovascular disease : stroke, myocardial infarction, angina pectoris, arrhythmias, congestive heart failure (NYHA Class \>2), or myocarditis within 6 months prior to first study drug administration.
• Patient with a history of organ transplant including stem cell allograft.
• Patients receiving or to be treated during the treatment period with one of the following forbidden treatment: Any anti-cancer systemic chemotherapy, targeted therapy or biological therapy including any immunotherapy not mentioned in this protocol; Any investigational agents other than Debio-1143; Radiation therapy; Live vaccines, Major surgery; Corticosteroids for any purpose other than to modulate symptoms from an event of clinical interest of suspected immunologic etiology. The use of physiologic doses of corticosteroids may be approved after consultation with the sponsor; Strong P-gp inhibitors or inducers.
• Patients with hypersensitivity to Pembrolizumab or any of its excipients.

Sponsors & Collaborators

• Centre Leon Berard: lead
• Merck Sharp & Dohme LLC: collaborator
• Debiopharm International SA: collaborator

Study Sites (1)

Centre Léon Bérard

Lyon, 69373, France

Location

Related Publications (1)

• Crawford N, Stott KJ, Sessler T, McCann C, McDaid W, Lees A, Latimer C, Fox JP, Munck JM, Smyth T, Shah A, Martins V, Lawler M, Dunne PD, Kerr EM, McDade SS, Coyle VM, Longley DB. Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer. Mol Cancer Ther. 2021 Sep;20(9):1627-1639. doi: 10.1158/1535-7163.MCT-20-1050. Epub 2021 Aug 13.

  PMID: 34389694 DERIVED

MeSH Terms

Conditions

Colonic Neoplasms; Rectal Neoplasms

Interventions

pembrolizumab; N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Philippe CASSIER, MD

  Centre Leon Berard

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The dose escalation part will follow a classical 3+3 design. 3 to 6 patients will be enrolled at each Dose Level depending of the number of Dose Limiting Toxicities observed.

Study Record Dates

• First Submitted: March 8, 2019
• First Posted: March 12, 2019
• Study Start: September 15, 2019
• Primary Completion: May 30, 2022
• Study Completion: June 8, 2022
• Last Updated: February 17, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)