Debio 1143 in Combination With Carboplatin and Paclitaxel in Patient With Advanced Solid Malignancies

A Phase I Study to Evaluate the Safety and Determine the Maximum Tolerated Dose (MTD) of Debio 1143 Combined With Carboplatin and Paclitaxel in Patients With Squamous Non-Small Cell Lung Cancer (NSCLC), Platinum-refractory Ovarian Cancer, and Basal-like/Claudin Low Triple Negative Breast Cancer (TNBC)

This is a two-part trial in patients with squamous non-small cell lung cancer (NSCLC), platinum (Pt)-refractory ovarian cancer, and basal-like/claudin low triple negative breast cancer (TNBC).

The primary objective of Part A is to determine the maximum tolerated dose (MTD) of Debio 1143 when administered to these patients in combination with full doses of paclitaxel and carboplatin.

The primary objective of Part B is to consolidate the safety profile of the recommended dose of Debio 1143 when administered to these patients in combination with full doses of paclitaxel and carboplatin.

Study Overview

• Status: Terminated
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: Part A: Debio 1143; Drug: Paclitaxel; Drug: Carboplatin; Drug: Part B: Debio 1143

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Dijon, France, 21079
    • Centre Georges Francois Leclerc
  • Lyon, France, 69008
    • Centre Léon Bérard
  • Paris, France, 75248
    • Institut Curie
  • Toulouse, France, 31052
    • Institut Claudius Regaud

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Meets protocol-specified criteria for qualification and contraception
• Is willing and able to remain confined in the study unit for the entire duration of each treatment period and comply with restrictions related to food, drink and medications
• Voluntarily consents to participate and provides written informed consent prior to any protocol-specific procedures

Exclusion Criteria:

• Has history or current use of over-the-counter medications, dietary supplements, or drugs (including nicotine and alcohol) outside protocol-specified parameters

• Has signs, symptoms or history of any condition that, per protocol or in the opinion of the investigator, might compromise:

  1. the safety or well-being of the participant or study staff;
  2. the safety or well-being of the participant's offspring (such as through pregnancy or breast-feeding); or
  3. the analysis of results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Debio 1143; Eligible participants receive Part A: Debio 1143 once daily for 5 consecutive days in each 21-day treatment cycle according to dose escalation rules (in combination with Paclitaxel and Carboplatin standard of care)	Drug: Part A: Debio 1143; Adaptive doses of Debio1143 oral capsules, between 50 and 400 mg until the recommended dose (RD) is determined.; Drug: Paclitaxel; Paclitaxel standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle, after pre-medication to prevent severe hypersensitivity reactions.; Drug: Carboplatin; Carboplatin standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle.
Experimental: Part B: Lung Cancer; Participants with Lung Cancer receive Part B: Debio 1143 once daily for 5 consecutive days in each 21-day treatment cycle (in combination with Paclitaxel and Carboplatin standard of care)	Drug: Paclitaxel; Paclitaxel standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle, after pre-medication to prevent severe hypersensitivity reactions.; Drug: Carboplatin; Carboplatin standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle.; Drug: Part B: Debio 1143; RD of Debio1143 oral capsules, once daily for five consecutive days starting on day 1 or 2 of each 21-day treatment cycle.
Experimental: Part B: Ovarian Cancer; Participants with Ovarian Cancer receive Part B: Debio 1143 once daily for 5 consecutive days in each 21-day treatment cycle (in combination with Paclitaxel and Carboplatin standard of care)	Drug: Paclitaxel; Paclitaxel standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle, after pre-medication to prevent severe hypersensitivity reactions.; Drug: Carboplatin; Carboplatin standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle.; Drug: Part B: Debio 1143; RD of Debio1143 oral capsules, once daily for five consecutive days starting on day 1 or 2 of each 21-day treatment cycle.
Experimental: Part B: Breast Cancer; Participants with Breast Cancer receive Part B: Debio 1143 once daily for 5 consecutive days in each 21-day treatment cycle (in combination with Paclitaxel and Carboplatin standard of care)	Drug: Paclitaxel; Paclitaxel standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle, after pre-medication to prevent severe hypersensitivity reactions.; Drug: Carboplatin; Carboplatin standard of care, intravenous (IV), once on day 1 or 2 of each 21-day treatment cycle.; Drug: Part B: Debio 1143; RD of Debio1143 oral capsules, once daily for five consecutive days starting on day 1 or 2 of each 21-day treatment cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Number of participants with dose-limiting toxicities	Categories: each Debio 1143 dose level and overall	up to 18 weeks
Part B: Percentage of participants with adverse events (AEs) and serious AEs (SAEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria		up to 18 weeks + 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Percentage of participants with AEs and serious adverse events (SAEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria	Categories: each Debio 1143 dose level and overall	up to 18 weeks + 28 days
Part A: Number of participants with change in vital signs	Categories: each Debio 1143 dose level and overall	up to 18 weeks
Part A: Number of participants with change in electrocardiogram (ECG)	Categories: each Debio 1143 dose level and overall	up to 18 weeks
Part A: Number of participants with change in Eastern Cooperative Oncology Group (ECOG) performance status (PS)	Categories: each Debio 1143 dose level and overall	up to 18 weeks
Part B: Number of participants with change in vital signs	Categories: each indication at the recommended dose (RD)	up to 18 weeks
Part B: Number of participants with change in electrocardiogram (ECG)	Categories: each indication at the recommended dose (RD)	up to 18 weeks
Part B: Number of participants with change in Eastern Cooperative Oncology Group (ECOG) performance status (PS)	Categories: each indication at the recommended dose (RD)	up to 18 weeks
Part A: Percentage of participants with incidence of laboratory abnormalities according to NCI-CTCAE criteria	Categories: each Debio 1143 dose level and overall	up to 18 weeks
Part B: Percentage of participants with incidence of laboratory abnormalities according to NCI-CTCAE criteria	Categories: each indication at the RD	up to 18 weeks
Part A: Percentage of participants with treatment discontinuations due to AEs and SAEs	Categories: each Debio 1143 dose level and overall	up to 18 weeks + 28 days
Part B: Percentage of participants with treatment discontinuations due to AEs and SAEs	Categories: each indication at the RD	up to 18 weeks + 28 days
Part A: Number of participants with change in left ventricular ejection fraction (LVEF)	Categories: each Debio 1143 dose level and overall	up to 18 weeks
Part B: Number of participants with change in left ventricular ejection fraction (LVEF)	Categories: each indication at the RD	up to 18 weeks
Part A: Number of participants with tumour response: disease control, change in tumour size from baseline and overall response	Categories: each Debio 1143 dose level and overall	up to 18 weeks
Part B: Number of participants with tumour response: disease control, change in tumour size from baseline and overall response	Categories: each indication at the RD	up to 18 weeks
Part A: Percentage of participants with progression-free survival (PFS) at 6 months	Categories: each Debio 1143 dose level and overall	at 6 months
Part B: Percentage of participants with progression-free survival (PFS) at 6 months	Categories: each indication at the RD	at 6 months
Part A: Percentage of participants with survival at 1 year	Categories: each Debio 1143 dose level and overall	at 12 months
Part B: Percentage of participants with survival at 1 year	Categories: each indication at the RD	at 12 months
Part B: Maximum concentration (Cmax) in the pharmacokinetic (PK) subset	Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Lowest concentration before the next dose (Ctrough) of Debio 1143 in the PK subset	Categories: alone and in combination with chemotherapy	up to 18 weeks
Part B: Time to maximum concentration (tmax) in the PK subset	Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Area under the concentration versus time curve from the beginning to a point in time (AUC0-t) in the PK subset	Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Area under the concentration versus time curve extrapolated to infinity (AUC∞) in the PK subset	Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Terminal rate constant (λz) in the PK subset	Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Apparent terminal half-life (t½) in the PK subset	Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Mean residence time (MRT) in the PK subset	Categories: Debio 1143 alone; Debio 1143 when administered with paclitaxel and carboplatin; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Apparent clearance (CL/F) of Debio 1143 in the PK subset	Categories: alone and in combination with chemotherapy	up to 18 weeks
Part B: Apparent volume of distribution during the terminal phase (Vz/F) of Debio 1143 in the PK subset	Categories: alone and in combination with chemotherapy	up to 18 weeks
Part B: Total amount of Debio 1143 excreted in urine (Ae) in the PK subset	Categories: alone and in combination with chemotherapy	up to 18 weeks
Part B: Total amount of Debio 1143 excreted in urine in the first 8 hours (Ae0-8) in the PK subset	Categories: alone and in combination with chemotherapy	up to 18 weeks
Part B: Total amount of Debio 1143 excreted in urine between 8 and 24 hours (Ae8-24) in the PK subset	Categories: alone and in combination with chemotherapy	up to 18 weeks
Part B: Renal clearance calculated as Ae/AUC∞ (CLR) of Debio 1143 in the PK subset	Categories: alone and in combination with chemotherapy	up to 18 weeks
Part B: Fraction of the dose excreted in urine calculated as Ae/dose (fe) of Debio 1143 in the PK subset	Categories: alone and in combination with chemotherapy	up to 18 weeks
Part B: Area under the concentration versus time curve in the first 12 hours (AUC0-12) in the PK subset	Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Total body clearance (CL) in the PK subset	Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Volume of distribution at steady-state (Vss) in the PK subset	Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Mean Residence Area under the concentration versus time curve (MR,AUC) in the PK subset	Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Mean Residence Maximum Concentration (MR,Cmax) in the PK subset	Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Platinum Refraction (PtR) in ovarian cancer participants included in the PK subset	Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Cmax in patients other than the PK subset	Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks
Part B: Concentration observed at time n (Cn) following Debio 1143 administration in patients other than the PK subset	Categories: paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered as chemotherapy alone; paclitaxel, 6αOH-paclitaxel (metabolite), and carboplatin (total and free Pt) when administered in combination with Debio 1143	up to 18 weeks

Collaborators and Investigators

• Sponsor: Debiopharm International SA
• Investigators: Study Chair: Jean-Pierre Delord, MD, Institut Claudius Regaud, Toulouse, France

Publications and helpful links

Helpful Links

• Site Debiopharm SA

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: June 21, 2013
• First Submitted That Met QC Criteria: August 27, 2013
• First Posted (Estimate): August 28, 2013

Study Record Updates

• Last Update Posted (Estimate): March 24, 2016
• Last Update Submitted That Met QC Criteria: March 23, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Carboplatin; Paclitaxel
• Other Study ID Numbers: Debio 1143-103; 2012-003676-40 (EudraCT Number)