Study of Debio 0932 in Patients With Advanced Solid Tumours or Lymphoma

Debiopharm

Status and phase: Completed; Phase 1

Conditions: Neoplasms; Lymphoma; Cancer; Solid Tumors

Treatments: Drug: Debio 0932

Study type: Interventional

Funder types: Industry

Identifiers

NCT01168752

Debio 0932-101

2009-017720-11 (EudraCT Number)

Details and patient eligibility

About

The purpose of this study is to determine the maximum tolerated dose of Debio 0932 when administered orally, every-other-day or daily during the first 30 days, in patients with solid tumours or lymphoma.

Full description

This is an open-label, non-randomised, dose-escalation phase I, pharmacokinetic and pharmacodynamic study in patients with advanced and/or refractory malignancies (solid tumours or lymphoma), to determine the maximum tolerated doses (MTD) of Debio 0932 administered orally every-other-day (schedule A) or every day (schedule B) and to assess its safety profile, pharmakokinetic, antitumor activity and pharmacodynamic biomarkers.

Increments used in dose escalation will be determined according to the maximum grade of treatment-related adverse events observed during the first 30-day treatment period of each schedule in the previous in the preceding dose level Once reaching the recommended dose (RD) for each schedule, up to 40 additional patients will be enrolled and treated at the RD of the retained schedule, as part of an expansion phase.

Enrollment: 81 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Histologically confirmed diagnosis of advanced solid tumours or lymphoma, except for primitive hepatocarcinoma for which radiological diagnosis only is permitted;
• Advanced or metastatic disease refractory to standard curative or palliative therapy or contraindication or have refused standard therapy,
• Measurable and/or evaluable disease,
• Age ≥ 18 years,
• ECOG performance ≤ 1
• Life expectancy ≥ 3 months,
• If female, neither pregnant or lactating,
• Negative pregnancy test for females at screening, preferably done within 1 week before Day 1 of treatment (not applicable to patients with bilateral oophorectomy and/or hysterectomy),
• Agreeing to use appropriate medically approved contraception (physical barrier contraception is recommended) from study entry to 6 months after the last day of treatment for the patient,
• Absolute neutrophil count ≥ 1,500/µL; platelets ≥ 100,000/µL; calculated creatinine clearance ≥ 60mL/min (calculated according to the formula of Cockroft and Gault); total bilirubin ≤ 1.5x ULN; AST/ALT ≤ 2.5x ULN. In patients with documented liver metastases, the AST/ALT may be ≤ 3.5x ULN; prothrombin time ≤1.5x ULN, kalemia, magnesemia and phosphatemia > LLN (Lower Limit of Normal)
• Able to render informed consent and to follow protocol requirements,
• Able to swallow capsules,
• Able to comply with scheduled plans, laboratory tests, and other study procedures.

Exclusion criteria

• Received investigational agents or systemic anti-cancer agents within 14 days of Day 1 of treatment, or 28 days for those agents with unknown elimination half-lives, or known elimination half-lives greater than 50 hours; or 6 weeks for Mitomycine C or for nitrosourea agents,

• Unresolved toxicity from previous treatment or previous investigational agents,

• Patients with history of prior radiation that potentially included the heart in the field (e.g. mantle),

• Cardiac exclusion criteria:

  • History of significant coronary artery disease or congestive heart failure that meets NYHA class III or IV, within 12 months (see Appendix D),
  • Significant cardiovascular dysfunction : pulmonary hypertension, right ventricular systolic dysfunction, aortic stenosis, mitral insufficiency > grade 2 and/or Left Ventricular Ejection fraction < 45% or < 55% if prior exposure to anthracyclines, based on MUGA or echocardiography,
  • Uncontrolled hypertension (Systolic > 150 or diastolic >100),
  • Permanent and uncontrolled cardiac rhythm disorders and clinical relevant abnormalities in 12-lead ECG/Holter, such as WPW (Wolff-Parkinson-White) syndrome, QRS > 120 msec, PR > 220 msec, heart rate < 50 bpm, Q wave, ST deviation, left bundle branch block, atrial fibrillation, flutter, tachysystoly.
  • Prolonged QTc interval > 450 msec in men and > 470 msec in women using Fridericia formula,
  • Congenital long QT syndrome,
  • Use of any medication associated with known QTc interval prolongation (a non-exhaustive list will be provided separately)

• Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C,

• Patients with uncontrolled brain metastases,

• Gastrointestinal diseases or disorders that could affect drug absorption such as diarrhoea, major abdominal surgery, significant bowel obstruction and/or gastrointestinal diseases that could alter the assessment of safety, including any of the following:

  • Irritable bowel syndrome
  • Ulcerative colitis
  • Crohn disease
  • Haemorrhagic coloproctitis

• Concurrent participation with any other anticancer therapy.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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81 participants in 2 patient groups

schedule A

Experimental group

Description:

Debio 0932 will be administered orally to sequential escalating dose cohorts, as an every-other-day schedule. Each dose level (DL) for each schedule will be determined according to the maximum grade of treatment-related AEs observed during the first 30 days treatment period (DLT period) in the previous DL. Dose-escalation could be undertaken only after a minimum of 3 (or 6 in case of DLT) patients have been followed up and evaluated for at least 1 DLT period.

Treatment:

Drug: Debio 0932

schedule B

Experimental group

Description:

Debio 0932 will be administered orally to sequential escalating dose cohorts, as a daily schedule. Each dose level (DL) for each schedule will be determined according to the maximum grade of treatment-related AEs observed during the first 30 days treatment period (DLT period) in the previous DL. Dose-escalation could be undertaken only after a minimum of 3 (or 6 in case of DLT) patients have been followed up and evaluated for at least 1 DLT period.

Treatment:

Drug: Debio 0932