Solid Tumors
Conditions
Interventions
Product Name: Debio 1143
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Debio 1143
Other descriptive name: DEBIO 1143
Concentra
Sponsors
Debiopharm International SA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: All patients must fulfil all the following criteria (both Parts A and B, unless specified otherwise): 1. Willing and able to sign a written informed consent form; 2. Male or female =18 years of age. 3. Histologically and/or cytologically confirmed advanced/ unresectable or metastatic solid tumor for one the following indications: a. SCLC b. SCCHN c. GI cancers, including esophageal, gastric, colorectal or pancreatobiliary with known MSI-H/MMRd or any other known DDRs abnormalities, including HRD d. Platinum-resistant* EOC, endometrial cancer, PPC or cervical cancer, with known MSI-H/ MMRd, hereditary/somatic mutations of the BRCA1 and BRCA2 genes or other known DNA DDRs abnormalities (incl. HRD) * Platinum-resistant is defined as relapse or progressive disease (PD) occurring within 1 to 6 months (180 days) after a platinum-containing chemotherapy. 4. 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) 5. 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) 6. Minimum washout periods since prior therapy until treatment start (C1D1) (in cases of more than one prior treatment type, whichever has the longest minimum period applies): a. 3 weeks for chemotherapy (6 weeks, specifically for nitrosoureas or mitomycin C containing regimens); b. 4 weeks for mAbs (other than previous PD-1/PD-L1), or live vaccines c. 3 weeks for prior RT (1 week in case of localized antalgic/hemostatic hypofractionated RT flash) d. 2 weeks for TKIs, hormonal therapy, other anti-cancer treatment not previously specified or investigational agents or previous anti-PD-1/PD-L1 mAbs e. 4 weeks for any major surgery f. Immunosuppressive medication: within 2 weeks, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological/replacement doses, which should never exceed 10 mg/d prednisone, or an equivalent corticosteroid 7. Measurable disease (Part B only) according to RECIST v1.1 or GCIC criteria in Cohort #4 (if applicable) and documented PD during or after prior PD-1/PD-L1 based therapy 8. ECOG Performance Status = 0 or 1 9. Adequate hematologic renal and hepatic function: a. absolute neutrophil count (ANC) = 1.5 x109/L, b. platelets = 100 x109/L, c. hemoglobin = 10.0 g/dL, d. AST and ALT = 3 x ULN, e. total bilirubin = 1.5 x ULN, f. serum creatinine = 1.5 x ULN, g. serum albumin = 30 g/L 10. Available archived tumor samples for biomarker analysis obtained after
Exclusion criteria
Exclusion criteria: Any of the following would render a patient ineligible for inclusion (in both Parts A and B, unless specified otherwise): 1. Thoracic or head and neck radiation >30 Gy within the 3 months prior to C1D1; 2. Have received, in total, more than 3 (i.e. Cohorts 1&2) or 4 (i.e. Cohorts 3&4) lines of prior systemic treatments (including adjuvant or neoadjuvant regimens if relapse within six months prior to C1D1); 3. Active moderate alcohol consumption, at screening, more than 100/140 grams of alcohol per week for female and male patients, respectively 4. Liver cirrhosis Child-Pugh score B or C 5. Prior treatment with an anti-CTLA-4 or anti-LAG3 in combination with PD-1/ PD-L1 CPI, unless discussed and agreed with the Sponsor 6. Prior treatment with SMAC mimetics 7. Prior PD-1/PD-L1 discontinuation due to severe immune-related toxicity, not resolved upon adequate steroids/immunosuppressive treatment 8. Requirement of concomitant treatment with any prohibited medication (See Appendix B: Prohibited medications and special Warnings) 9. Ongoing toxicity from prior administration of any other investigational drug and/or anti-cancer treatment of > Grade 1 NCI-CTCAE v5.0 before treatment start (except for grade 2 alopecia, stable sensory neuropathy, or any endocrinopathy adequately managed by replacement hormonal therapy) 10. Patients with known history of: a. Uncontrolled or symptomatic angina or myocardial infarction, within the last 12 months prior to C1D1 b. Elevated (>ULN) troponins (T or I) or creatine phosphokinase (CPK) > 1.5xULN during screening c. Symptomatic intestinal sub-occlusion d. Infection, active or latent by human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) e. Ongoing arrhythmias requiring treatment, including asymptomatic QTc interval as corrected by Fridericia (F) >480 msec f. In patients previously treated with anthracycline-containing chemotherapy or thoracic RT, nonadequate cardiac function with left ventricular ejection fraction (LVEF) <50%, measured by an echocardiogram (ECHO) or a multigated acquisition (MUGA) as per institutional standards g. Active rheumatoid arthritis, active inflammatory bowel disease (IBD), primary sclerosing cholangitis, autoimmune hepatitis, systemic lupus erythematous (SLE), multiple sclerosis or any other ongoing autoimmune disease requiring systemic treatment (excluding vitiligo, mild cutaneous psoriasis and asymptomatic autoimmune endocrinopathy well controlled under hormonal replacement therapy) h. Evidence of active, non–infectious pneumonitis or a history of interstitial lung disease 11. Evidence or clinical suspicion of active bleeding or requirement of red blood cell (RBC) transfusions within 4 weeks prior to C1D1 12. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Debio 1143 or nivolumab or their constituents 13. History of another malignancy than the primary tumor within the last 3 years prior to C1D1, except: com
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part A: The primary objective of the dose-optimization part of the study is to determine the RP2D taking into account DLT/s in Cycle 1, overall safety/tolerability and PK, by optimizing doses of Debio 1143 when combined with the standard dose of nivolumab, as well as treatment compliance in patients with advanced solid malignancies who failed prior systemic standard treatments. Part B: The primary objective of the basket trial is 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 patient cohort. ; Secondary Objective: Part A: For the dose-optimization part, secondary objectives are to assess the: 1. PK disposition of Debio 1143 (including its metabolite Debio 1143-MET1) and nivolumab when administered in combination. 2. Anti-tumor activity of Debio 1143 in combination with nivolumab in patients with advanced solid malignancies. Part B: For the basket trial, secondary objectives are to assess the: 1. Safety and tolerability of the RP2D of Debio 1143 when given in combination with nivolumab in patients with advanced solid malignancies. 2. PK disposition of Debio 1143 (and its metabolite Debio 1143-MET1) and nivolumab when administered in combination. ; Primary end point(s): PART A: The primary endpoint of part A is the RP2D of Debio 1143 when combined with the standard dose of nivolumab, in patients with advanced solid malignancies who received prior systemic standard treatment and failed a prior PD-1/PD-L1-containing treatment, as per DLT occurrence in less than one-third of evaluable treated patients at the RP2D dose | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints for both study parts (unless otherwise specified) are: Incidence and severity of TEAEs and clinical laboratory abnormalities, according to NCI-CTCAE version 5.0 criteria -Changes in vital signs: systolic/diastolic blood pressure, heart rate (both after at least 5 minutes of supine rest), temperature, and weight; ECG and ECOG-PS -Incidence of premature treatment discontinuations and treatment modifications due to AEs and laboratory abnormalities (i.e., treatment compliance) -Tumor response determined according to RECIST v1.1 and/or GCIG criteria (Cohort 4, if applicable): - Confirmed (Part A) and unconfirmed (Parts A and B)ORR - Disease control rate (DCR), defined as any response, partial or complete (PR or CR) + stable disease (SD) -Time-related endpoints as median time to response, median DOR, median PFS, PFS rate at 6, 12 and 18 months, median OS, OS rate at 12 months and 18 months (if data allow) PK parameters of Debio 1143 and Debio 1143-MET1 as defined in the available population PK model and, if appropriate, post-hoc estimates of areas under the curve (AUCs), Cmax, and Cmin; serum concentration versus time profiles of nivolumab and, if deemed appropriate, relevant nivolumab PK parameters derived from a population PK model. ;Timepoint(s) of evaluation of this end point: These will be done at various timepoints throughout the study. | — |
Countries
France, Spain, United States
Contacts
Public ContactClinical department
Debiopharm International SA
Outcome results
None listed