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

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.

• monalizumab (Drug), also known as Anti-NKG2A, IPH2201: During phase 1, patients received monalizumab, IV, at the dose of 1, 2 or 4mg/kg, as a single agent during 4 weeks and thereafter combined with ibrutinib 420 mg, orally, once daily, during 52 weeks. During phase 2, patients received monalizumab, IV, at the dose recommended upon completion of phase 1, combined with ibrutinib 420 mg orally, once daily, from the first cycle, during 52 weeks. In both parts of the trial, the first 4 administrations of monalizumab (from week 0 to week 6) occured every 2 weeks. From the 5th administration monalizumab was administered every 4 weeks.

Primary outcomes

• Number of Dose Limiting Toxicities [8 weeks]: Number of dose-limiting toxicities, measured during the phase 1, dose escalation, part of the study.
• 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.

Secondary outcomes

• 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).
• 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.
• 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.
• 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.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Number of Dose Limiting Toxicities (Primary), Number, Dose Limiting Toxicy: Phase 1 Level 1 - 1 mg/kg 0; Phase 1 Level 2 - 2 mg/kg 1; Phase 1 Level 3 - 4 mg/kg 2
• Rate of Complete Response (CR) (Primary), Count of participants, Participants: Phase 1 Level 1 - 1 mg/kg 1; Phase 1 Level 2 - 2 mg/kg 1; Phase 1 Level 3 - 4 mg/kg 0; Phase 2 RP2D - 2 mg/kg 0
• Best Overall Response / Remission Rates (Secondary), Count of participants, Participants: Phase 1 Level 1 - 1 mg/kg 1; Phase 1 Level 2 - 2 mg/kg 1; Phase 1 Level 3 - 4 mg/kg 0; Phase 2 RP2D - 2 mg/kg 0
• Duration of Remission (Secondary), Median, Month: Efficacy Population NA (NA to NA)
• Progression Free Survival (Secondary), Median, Month: ITT / Safety Population NA (NA to NA)
• Overall Survival (Secondary), Median, Month: All ITT / Safety Population NA (NA to NA)

Adverse events

Time frame: The occurrences of Adverse Events were recorded from the time of signed informed consent until the end of the patient's participation to the trial (up to 24 months).

Serious adverse events by term

Other adverse events by term

99 more terms not shown.

Limitations and caveats: Due to early termination some of the secondary endpoints could not be evaluated.

• Statistical Analysis Plan (PDF, 2019-03-08)
• Study Protocol (PDF, 2016-08-12)

• Kerry A Rogers, MD, Principal investigator, Ohio State University