GDC-0152

Iris Chan, M.D., Ph.D.

The study consists of two stages. In Stage 1, maximum tolerated dose (MTD) will be determined. In Stage 2, additional patients will be treated at the MTD of GDC-0152.

A Study of the Safety and Pharmacokinetics of GDC-0152, Administered Intravenously to Patients With Locally Advanced or Metastatic Malignancies

A Phase Ia, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of GDC-0152, an IAP Protein Antagonist, Administered Intravenously to Patients With Locally Advanced or Metastatic Malignancies

Genentech, Inc.

Neoplasms

All Conditions

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

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

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

DEBIO1143

Philippe CASSIER, MD

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.

All patient wil receive a combinaison of Pembrolizumab and Debio 1143. Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

Debio 1143 is an investigational, oral monovalent second mitochondrial-derived activator of caspases (SMAC) mimetic designed to promote programmed cell death (apoptosis) in tumor cells and anti-tumour immunity. By antagonizing the activity of inhibitor of apoptosis proteins (IAPs (X-linked IAP \[XIAP\], cellular IAP 1 \[cIAP1\], cellular IAP 2 \[cIAP2\] and melanoma-linked IAP \[ML-IAP\])), Smac mimetics are an interesting treatment approach for cancer that may foster better tumor responses to chemo/radiotherapy- and/or immuno-therapy.

A Dose escalation part (n= up to 18 patients ) aiming to define the Maximum Tolerated Dose and the the Recommended Dose for Phase 2 of the proposed combination. A classical 3+3 design will be used with a fixed dose of Pembrolizumab (200 mg, intravenous , to be administered on Day 1 of every 3-week cycle i.e. Q3W) and 3 escalating dose level of Debio 1143 administered daily for 14 days over a 21-day cycle period.

There will be a 24-hour delay between the first and subsequent patients enrolled in each DL cohort to maximize the safety of enrolled patients.

An extension part (n=28 patients: 14 patients per cohort) aiming to evaluate the clinical activity of the proposed combination.

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.

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

CATRIPCA - A Phase I Study of PD1 Monoclonal Antibody (Pembrolizumab) In Combination With a IAP Antagonist (Debio 1143) In (Exocrine) Pancreatic And Colorectal Non MSI-high Advanced/Metastatic Adenocarcinoma.

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

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

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

The duration of response will be measured from the time of first documented response (Complete Response or Partial Response as per RECIST V1.1) until the first documented disease progression or death due to underlying cancer, and censored at the date of the last available tumor assessment.

The Clinical Benefit Rate will be defined as the proportion of patients with Complete Response, Partial Response or stable disease according to RECIST V1.1.

The tumor-response efficacy endpoints described above will be evaluated by investigator-assessed RECIST v1.1 (Eisenhauer et al. E J Cancer 2009).

The tumor-response efficacy endpoints described above will be evaluated by modified criteria for immunotherapies iRECIST (Seymour et al. Lancet Oncol 2017).

Progression-Free Survival (PFS) will be measured from the C1D1 until the date of event defined as the first documented progression or death from any cause. Patients with no event at the time of the analysis will be censored at the date of the last available tumor assessment.

Overall survival (OS) will measured from C1D1 to the date of death from any cause. Patients who are alive at the time of analysis will be censored at the date of the last contact.

The assessment of safety will be based mainly on the frequency of adverse events based on the common toxicity criteria (CTCAE v5.0) grade.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of the Safety and Pharmacokinetics of GDC-0152, Administered Intravenously to Patients With Locally Advanced or Metastatic Malignancies	NCT00977067	Solid Cancers	GDC-0152	18 Years -	Genentech, Inc.
A Study of the Safety and Pharmacokinetics of GDC-0152, Administered Intravenously to Patients With Locally Advanced or Metastatic Malignancies	NCT00977067	Solid Cancers	GDC-0152	18 Years -	Genentech, Inc.
Pembrolizumab In Combination With Debio 1143 In Pancreatic and Colorectal Advanced/Metastatic Adenocarcinoma	NCT03871959	Adenocarcinoma ... Adenocarcinoma ... Adenocarcinoma ...	Pembrolizumab DEBIO1143	18 Years -	Centre Leon Berard

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