Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143 (SMARTPLUS-106)

Debiopharm

Status and phase: Completed; Phase 2; Phase 1

Conditions: Solid Tumor

Treatments: Drug: Nivolumab; Drug: Debio 1143

Study type: Interventional

Funder types: Industry

Identifiers

NCT04122625

Debio 1143-106

2018-003546-16 (EudraCT Number)

Details and patient eligibility

About

Part A (dose-optimization)- to determine the recommended phase 2 dose (RP2D) taking into account dose-limiting toxicity (DLT/s) in Cycle 1, overall safety/tolerability and pharmacokinetic (PK), by optimizing doses of Debio 1143 when combined with the standard dose of nivolumab, as well as treatment compliance in participants with advanced solid malignancies who failed prior systemic standard treatments.

Part B (basket trial)- to evaluate the preliminary anti-tumor activity of Debio 1143 at the RP2D in combination with nivolumab at the standard dose, overall and in each participant cohort (Cohort 1: small cell lung cancer [SCLC]; Cohort 2: squamous cell carcinoma of the head and neck [SCCHN]; Cohort 3: gastrointestinal (GI) cancers with known microsatellite instability-high/mismatch repair deficiency (MSI-H/MMRd) or other deoxyribonucleic acid (DNA) damage repair (DDR) abnormalities, including homologous recombination deficiency (HRD); Cohort 4: platinum-resistant epithelial ovarian cancer [EOC], endometrial cancer, primary peritoneal cancer (PPC) or cervical cancer, with known MSIH/MMRd, hereditary/somatic mutations of the breast cancer 1 (BRCA1) and BRCA2 genes or other DNA DDR abnormalities (incl. HRD).

Enrollment: 46 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Have received at least one prior line of standard systemic chemotherapy in the advanced/unresectable cancer setting (standard adjuvant/neoadjuvant treatment is acceptable if relapse occurred within six months of treatment end)
• Have progressed or relapsed during or after a prior anti-programmed cell death-1 (PD-1)/ programmed cell death-ligand 1 (PD-L1)-based treatment, given either as a single agent or in combination with standard/approved chemotherapy, tyrosine kinase inhibitors (TKIs), radiotherapy (RT) or other monoclonal antibodies (mAbs) that are not known to modulate/inhibit immune checkpoints (CPIs)
• Measurable disease (Part B only) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or Gynecologic Cancer Intergroup (GCIG) criteria in Cohort #4 of Part B (if applicable) and documented PD during or after prior PD-1/PD-L1 based therapy

Exclusion criteria

• Thoracic or head and neck radiation >30 gray (Gy) within the 3 months prior to Cycle 1 Day 1 (C1D1)
• Have received, in total, more than 3 (i.e., Cohorts 1 & 2) or 4 (i.e., Cohorts 3 & 4) lines of prior systemic treatments in Part B (including adjuvant or neoadjuvant regimens if relapse within six months prior to C1D1)
• Liver cirrhosis Child-Pugh score B or C

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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46 participants in 6 patient groups

Part A - Debio 1143 150 mg + Nivolumab

Experimental group

Description:

Participants received Debio 1143, 150 milligrams (mg) capsules, orally once on Days 1 to 10 and Days 15 to 24 of each 28-day treatment cycle along with nivolumab 240 mg, intravenous (IV) infusion on Days 1 and 15 of each 28-day treatment cycle allowed for a maximum of 26 cycles.

Treatment:

Drug: Nivolumab

Drug: Debio 1143

Part A - Debio 1143 200 mg + Nivolumab

Experimental group

Description:

Participants received Debio 1143, 200 mg capsules, orally once on Days 1 to 10 and Days 15 to 24 of each 28-day treatment cycle along with nivolumab 240 mg, IV infusion on Days 1 and 15 of each 28-day treatment cycle allowed for a maximum of 26 cycles.

Treatment:

Drug: Nivolumab

Drug: Debio 1143

Part B - Cohort 1 (SCLC): Debio 1143 200 mg + Nivolumab

Experimental group

Description:

Participants with small-cell lung cancer (SCLC) received Debio 1143, 200 mg capsules, orally once on Days 1 to 28 in each 28-day treatment cycle along with nivolumab 240 mg, IV infusion on Days 1 and 15 of each 28-day treatment cycle allowed for a maximum of 26 cycles.

Treatment:

Drug: Nivolumab

Drug: Debio 1143

Part B - Cohort 2 (SCCHN): Debio 1143 200 mg + Nivolumab

Experimental group

Description:

Participants with squamous cell carcinoma of the head and neck (SCCHN) received Debio 1143, 200 mg capsules, orally once on Days 1 to 28 in each 28-day treatment cycle along with nivolumab 240 mg, IV infusion on Days 1 and 15 of each 28-day treatment cycle allowed for a maximum of 26 cycles.

Treatment:

Drug: Nivolumab

Drug: Debio 1143

Part B - Cohort 3 (GI Cancers): Debio 1143 200 mg + Nivolumab

Experimental group

Description:

Participants with gastrointestinal (GI) cancers received Debio 1143, 200 mg capsules, orally once on Days 1 to 28 in each 28-day treatment cycle along with nivolumab 240 mg, IV infusion on Days 1 and 15 of each 28-day treatment cycle allowed for a maximum of 26 cycles.

Treatment:

Drug: Nivolumab

Drug: Debio 1143

Part B - Cohort 4 (Gynecologic Cancers): Debio 1143 200 mg + Nivolumab

Experimental group

Description:

Participants with gynecologic cancers received Debio 1143, 200 mg capsules, orally once on Days 1 to 28 in each 28-day treatment cycle along with nivolumab 240 mg, IV infusion on Days 1 and 15 of each 28-day treatment cycle allowed for a maximum of 26 cycles.

Treatment:

Drug: Nivolumab

Drug: Debio 1143