Brentuximab Vedotin in Refractory/Relapsed Hodgkin Lymphoma Treated by ICE

Phase I/II Feasibility Study of Brentuximab Vedotin in Refractory / Relapsed Hodgkin Lymphoma Patients Who Are Treated by Chemotherapy (ICE) in Second Line and Eligible for Autologous Transplantation

This study is designed as a phase Ib/II trial. The first part (phase Ib) is a dose escalation design to explore the safety and assess the recommended phase 2 dose of Brentuximab Vedotin in Hodgkin lymphoma patients treated with ICE regimen.

The second part, depending on the selected dose after the completion of phase Ib part of the study, will further explore safety in addition to efficacy of the recommended dose of Brentuximab Vedotin in a selected population of patients treated with ICE with Hodgkin lymphoma.

PHASE I:

3 cycles of Brentuximab Vedotin ICE every 3 weeks and one cycle of Brentuximab Vedotin alone at the doses described below.

Cohorts of between three and six evaluable patients will be recruited at each dose level.

Dose escalation rules:

Treat 3 patients at level K

1. If 0 patients experience dose-limiting toxicity (DLT), escalate to dose K+1
2. If 2 or more patients experience DLT, de-escalate to level K-1
3. If 1 patient experiences DLT, treat 3 more patients at dose level K A. If 1 of 6 experiences DLT, escalate to dose level K+1 B. If 2 or more of 6 experiences DLT, de-escalate to level K-1 Dose escalation will begin at level K.

Level K:

Brentuximab Vedotin: 1.2 mg/kg (cycle 1-3), 1.8 mg/kg (cycle 4) ICE (cycle 1-3): Etoposide 100 mg/m² (day1 to 3); Carboplatine max 800mg (day 2); Ifosfamide + Mesna 5 g/m² (day 2)

Level K -1:

Brentuximab Vedotin: 0.8 mg/kg (cycle 1-3), 1.8 mg/kg (cycle 4) ICE (cycle 1-3): Etoposide 100 mg/m² (day1 to 3); Carboplatine max 800mg (day 2); Ifosfamide + Mesna 5 g/m² (day 2)

Level K +1:

Brentuximab Vedotin: 1.8 mg/kg (cycle 1-3), 1.8 mg/kg (cycle 4) ICE (cycle 1-3): Etoposide 100 mg/m² (day1 to 3); Carboplatine max 800mg (day 2); Ifosfamide + Mesna 5 g/m² (day 2)

Dose finding rule:

Provisional dose levels are listed in previous tables. Dose-escalation will continue until Maximal Tolerated Dose (MTD) or Recommended Phase 2 Dose (RP2D) is reached or the full doses of BV and ICE are delivered without DLT

PHASE II:

3 cycles of Brentuximab Vedotin + ICE every 3 weeks and one cycle Brentuximab Vedotin alone.

The recommended dose of BV and ICE will be determined by the phase I Brentuximab Vedotin: MTD mg/kg (cycle 1-3), 1.8 mg/kg (cycle 4) ICE (cycle 1-3): Etoposide 100 mg/m² (day1 to 3); Carboplatine max 800mg (day 2); Ifosfamide + Mesna 5 g/m² (day 2) The recommended dose of BV and ICE will be determined by the phase I.

Inclusion Criteria:

• Histologically confirmed cluster of differentiation antigen 30 + (CD30+) HL, primarily refractory to first line chemotherapy or in first relapse after any polychemotherapy regimen
• Measurable disease defined as at least one single node or tumor lesion on CT scan > 1.5 cm
• Fluorodeoxyglucose (FDG)-PET/ CT realized at relapse and positive.
• Age ≥ 18 years and up to 65 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2 (see appendix 19.5)
• Life expectancy of > 3 months with treatment
• No major organ dysfunction, unless HL-related
• Normal cardiac and pulmonary function for auto transplantation
• Total bilirubin < 1.5 x ULN (unless due to lymphoma involvement of the liver or a known history of Gilbert's syndrome)
• Alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2 x ULN (unless due to lymphoma involvement of the liver : ≤ 5 x ULN)
• Creatinine clearance > 60 mL/min
• Absolute neutrophil count ≥ 1.5x109/L, unless caused by diffuse bone marrow infiltration by the HL
• Platelets ≥ 100x109/L, unless caused by diffuse bone marrow infiltration by the HL
• Hemoglobin must be ≥ 8g/dL
• Written informed consent
• Able to adhere to the study visit schedule and other protocol requirements
• Eligible for high dose chemotherapy and autologous peripheral blood stem cell transplantation
• Resolution of toxicities from first-line therapy
• Female patient is either post-menopausal for at least 1 year before the screening visit or surgically sterile or if of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 6 months after the last dose of study drug, or agrees to completely abstain from heterosexual intercourse.
• Male patients, even if surgically sterilized, (i.e., status post vasectomy) agree to practice effective barrier contraception during the entire study period and through 6 months after the last dose of study drug, or agrees to completely abstain from heterosexual intercourse.

Exclusion Criteria:

• Peripheral sensory or motor neuropathy grade ≥ 2

• Any chemotherapy, radiotherapy, immunotherapy or investigational, therapy for treatment of lymphoma within 28 days prior Cycle1 Day1

• Patient who have been treated by first line of treatment with brentuximab vedotin alone or in combination

• Female patients who are both lactating and breast feeding or have a positive serum pregnancy test during the screening period or a positive pregnancy test 4 days prior the start of study drug

• Patients with active, uncontrolled infections (requiring systemic antibiotics within two weeks prior to treatment)

• Prior history of another cancer unless the subject has been free of the disease for ≥ 3 years (with the exception of non-melanoma skin cancer, completely resected melanoma TNMpT1 or carcinoma in situ of the uterine cervix)

• Known cerebral or meningeal disease (HL or any other etiology), including signs or symptoms of Progressive multifocal leukoencephalopathy

• Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin.

• Known history of human immunodeficiency virus (HIV), or known active Hepatitis C Virus, or active Hepatitis B Virus (HBV) infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.

• Patients with a psychiatric disorder that would preclude compliance with drug delivery

• Patients who have any severe and/or uncontrolled medical condition or other conditions that could affect their participation in the study such as:

  1. unstable angina pectoris, symptomatic congestive heart failure (NYHA II, III, IV), myocardial infarction ≤ 2 years prior to first study drug administration, serious uncontrolled cardiac arrhythmia, angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
  2. cerebrovascular accident ≤ 6 months before study drug start recent evidence (within 6 months before first dose of study drug)
  3. a left-ventricular ejection fraction <50%
  4. severely impaired pulmonary function as defined as spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) that is 50% or less of the normal predicted value and/or O2 saturation that is 90% or less at rest on room air
  5. any active (acute or chronic) or uncontrolled disorders that impair the ability to evaluate the patient or for the patient to complete the study
  6. any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 2 weeks prior to first study drug dose
  7. nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by this study drug, such as severe hypertension that is not controlled with medical management and thyroid abnormalities when thyroid function cannot be maintained in the normal range