Combination Study of IPH2201 (Monalizumab) With Ibrutinib in Relapsed, Refractory or Previously Untreated CLL

Phase 1

Terminated

Conditions: Chronic Lymphocytic Leukemia

Interventions: Drug: monalizumab

Registration Number: NCT02557516

Lead Sponsor: Innate Pharma

Brief Summary: Combination study of monalizumab (IPH2201) with Ibrutinib in relapsed, refractory or previously untreated Chronic Lymphocytic Leukemia (CLL) patients in 2 parts :

* phase 1 : a 3+3 design to assess the Maximum Tolerated Dose (MTD)

* phase 2: to evaluate the anti-leukemic activity of the combination

Detailed Description: This trial was designated to test the hypothesis that the combination of ibrutinib and IPH2201 will result in a substantial complete response (CR) rate, especially CR without minimal residual disease (MRD), as this has been shown to be associated with long-term clinical benefit.

Up to 45 patients were planned to be enrolled. During the phase 1 part a 3+3 dose escalation design was employed. Four doses were planned to be assessed if the Maximum Tolerated Dose (MTD) was not previously reached: 1, 2, 4 and 10 mg/kg.

During phase 2 part, patients received monalizumab in combination with ibrutinib; monalizumab was given at the dose recommended upon completion of the phase I portion.

The primary objective of the phase 1 was to assess the safety of monalizumab given intravenously as a single agent and in combination with ibrutinib in patients with relapsed, refractory or previously untreated Chronic Lymphocytic Leukemia.

The primary objective of the phase 2 was to evaluate the anti-leukemic activity of the combination of monalizumab and ibrutinib in patients with relapsed, refractory or previously untreated Chronic Lymphocytic Leukemia.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Confirmed diagnosis of Chronic Lymphocytic Leukemia (CLL)
Relapsed, refractory or previously untreated CLL
CLL requiring treatment; patients must be eligible for ibrutinib therapy
Age > = 18 years
Eastern Cooperative Oncology Group performance status of 0-2
Life expectancy > = 3 months
Adequate liver and renal function
Negative serum pregnancy test within 72 hours before starting study treatment in women with childbearing potential. Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of the study participation
Ability to understand a written informed and consent document
Signed informed consent prior to any protocol-specific procedures

Exclusion Criteria

Patients who have previously received ibrutinib or another inhibitor of Bruton's tyrosine kinase (BTK)
History of allergic reactions attributed to compounds or similar chemical or biological composition to ibrutinib
Central nervous system involvement of the CLL
Abnormal hematological function which is not due to bone marrow failure related to the CLL
Patients requiring a treatment by oral vitamin K antagonists
Serious uncontrolled medical disorder
Medical condition or organ system dysfunction which, in the investigator opinion, could interfere with absorption or metabolism of ibrutinib
Moderate or severe hepatic impairment
Active auto-immune disease
Abnormal cardiac status
Pregnant women are excluded from study
Current active infectious disease
History of another malignancy within 3 years
History of allogeneic stem cell or solid organ transplantation

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1 Level 1 - 1 mg/kg	monalizumab	In phase 1, Monalizumab given at the first dose level of 1 mg/kg.
Phase 1 Level 3 - 4 mg/kg	monalizumab	In phase 1, Monalizumab given at the third dose level of 4 mg/kg.
Phase 1 Level 2 - 2 mg/kg	monalizumab	In phase 1, Monalizumab given at the second dose level of 2 mg/kg.
Phase 2 RP2D - 2 mg/kg	monalizumab	In phase 2, Monalizumab given at the Recommended Phase 2 Dose (RP2D) of 2 mg/kg, selected by a safety committee.

Primary Outcome Measures

Name	Time	Method
Rate of Complete Response (CR)	CR assessed 52 weeks after the beginning of combination treatment	The rate of complete response (CR) was evaluated using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) grading scale and confirmed by a bone marrow biopsy. Per International Workshop on Chronic Lymphocytic Leukemia (IWCLL), Complete Response (CR) is defined as lymphocytes \<4x109/l, absence of lymphadenopathy, hepatomegaly and splenomegaly at CT scan, no constitutional symptoms, no cytopenia, normocellular bone marrow. Partial Response (PR) is a reduction \> 50% in lymphocytes, lymphadenopathy, spleen or liver, no cytopenia. PD if appearance of any new lesion, or increase in lymphocytes \> 50%, or occurrence of cytopenia attributable to CLL.
Number of Dose Limiting Toxicities	8 weeks	Number of dose-limiting toxicities, measured during the phase 1, dose escalation, part of the study.

Secondary Outcome Measures

Name	Time	Method
Best Overall Response / Remission Rates	From beginning of study drug treatment to the end of study (up to 24 months)	Measure of best overall response at any time during the study. cCR: confirmed complete response/remission; uCR: unconfirmed complete response / remission; PR: partial response/remission; SD: stable disease; PD: progressive disease. Per International Workshop on Chronic Lymphocytic Leukemia (IWCLL), Complete Response (CR) is defined as lymphocytes \<4x109/l, absence of lymphadenopathy, hepatomegaly and splenomegaly at CT scan, no constitutional symptoms, no cytopenia, normocellular bone marrow. Partial Response (PR) is a reduction \> 50% in lymphocytes, lymphadenopathy, spleen or liver, no cytopenia. PD if appearance of any new lesion, or increase in lymphocytes \> 50%, or occurrence of cytopenia attributable to CLL. In order to have a confirmed CR (cCR), the CR must be confirmed by a scan and a bone marrow assessment assessed at least 2 months after the first occurrence of CR. Otherwise it would be an unconfirmed CR (uCR).
Progression Free Survival	Up to 24 months	The Progression Free Survival (PFS) is defined as the time from first dose administration until the occurrence of progressive disease, relapsed disease or death from any cause. Patients without an event at the time of the analyse were censored at his or her last disease assessment date. Patients with no post-Baseline assessment were censored at the day of the first dose administration.
Duration of Remission	Up to 24 months	The duration of remission (DOR) is defined as the time from the date of first evaluation of the remission (cCR, uCR or PR) to the first documentation of progressive disease, relapsed disease or death. In case an assessment of progressive / relapsed disease or death does not exist, the DOR was censored at the time of the last disease assessment date. The DOR was calculated only for the patients with a remission that was assessed at 52 weeks.
Overall Survival	Up to 24 months.	The overall survival (OS) is defined as the time from first dose administration until death from any cause. Alive patients were censored at the most recent date they were known to be alive. Subjects with no assessment post-Baseline were censored at the day of the first dose administration.