A Phase 1b/2 Study of IPI-145 Plus FCR in Previously Untreated, Younger Patients With CLL

Study Overview
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Brief Summary
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This research study is evaluating a new drug called IPI-145 in combination with the standard drugs fludarabine, cyclophosphamide, and rituximab (FCR), as a possible treatment for chronic lymphocytic leukemia (CLL).

Detailed Description
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Patients who fulfill eligibility criteria will be entered into the trial to receive IPI-145 in combination with the standard drugs fludarabine, cyclophosphamide, and rituximab (FCR). After the screening procedures confirm participation in the research study: Phase I The investigators are looking for the highest dose of the combination of study drugs that can be administered safely without severe or unmanageable side effects in participants that have CLL. Not everyone who participates in this research study will receive the same dose of the study drug. The dose given will depend on the number of participants who have been enrolled in the study prior and how well the dose was tolerated. Phase II: Patients treated with IPI-145 at the Recommended Phase II Dose (RP2D) + fludarabine, cyclophosphamide, rituximab (FCR) with standard dosing.

Official Title
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A Phase 1b/2 Study of IPI-145 in Combination With Fludarabine, Cyclophosphamide, and Rituximab (iFCR) in Previously Untreated, Younger Patients With Chronic Lymphocytic Leukemia.

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: IPI-145
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: confirmed diagnosis of CLL and an indication for treatment as per IW-CLL 2008 criteria no prior therapy for CLL age 18-65 -- ECOG performance status ≤1 Exclusion Criteria: May not be receiving any other study agents Known CNS involvement Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study because IPI-145 has the potential for teratogenic or abortifacient effects. Individuals with a history of a different malignancy are ineligible except for the following circumstances. disease-free for at least 5 years and deemed to be at low risk for recurrence. Individuals with the following cancers are eligible if diagnosed and treated with curative intent within the past 5 years: cervical cancer in situ, localized prostate cancer, and basal cell or squamous cell carcinoma of the skin HIV-positive individuals, because of the potential for pharmacokinetic interactions with IPI-145 Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN); direct bilirubin >1.5 x ULN, unless due to hemolysis or Gilbert's syndrome Inadequate renal function defined by serum creatinine >1.5 x ULN. Baseline QTcF >480 ms. NOTE: This criterion does not apply to patients with a left bundle branch block Concurrent treatment with any agent known to prolong the QTc interval Patients with a history of active tuberculosis within the preceding two years. Patients who have had a venous thromboembolic event (e.g., PE/DVT) requiring anticoagulation and who meet any of the following criteria: Have been on a stable dose of anticoagulation for <1 month Have had a Grade 2, 3 or 4 hemorrhage in the last 30 days Are experiencing continued symptoms from their event History of alcohol abuse, chronic hepatitis, or other chronic liver disease (other than direct CLL liver involvement) Foods or medications that are strong or moderate inhibitors or inducers of CYP3A taken within 1 week prior to study treatment and for the duration of the study Unable to receive prophylactic treatment for pneumocystis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IPI-145<br>Phase I-Dose escalation will occur using a standard 3-3 dose escalation beginning in dose level 1 with dose cohorts and escalation. Each treatment cycle lasts 28 days (except cycle 1, which is 35 days) during which time IPI-145 will be taken twice daily. The study begins with 1 week of IPI-145 monotherapy. Fludarabine, cyclophosphamide, rituximab (iFCR) - FCR will subsequently be introduced after 1 week and administered at standard dosing for up to 6 cycles, with dose reductions permitted. IPI-145 will be continued through the course of chemotherapy and for up to 2 years maintenance after completing chemotherapy Phase II - 20 additional patients treated with IPI-145 at the Recommended Phase II Dose (RP2D) + fludarabine, cyclophosphamide, rituximab (FCR) with standard dosing. | Drug: IPI-145<br>* oral PI3K delta/gamma inhibitor<br>Drug: Fludarabine<br>* intravenous chemotherapy<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* intravenous chemotherapy<br>* Other names: Neosar®;Drug: Rituximab<br>* intravenous immunotherapy<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) During Phase I | To assess the safety of IPI145 in combination with FCR in previously untreated younger patients with CLL. DLT is based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. DLT refers to toxicities experienced at any time during the study treatment, defined as Grade 3 or greater hematologic toxicity (except Grade 3 or Grade 4 neutropenia or thrombocytopenia that lasts less than or equal to 10 days off treatment), any Grade 3 or greater non-hematologic toxicity (except Grade 3 or greater nausea, vomiting, diarrhea, Grade 3 infusion reactions), Grade 3 asymptomatic laboratory abnormalities that improve to grade 2 or less within 3 days, Inability to receive day 1 therapy of Cycle 2 even after a three week treatment delay due to drug related toxicity from prior cycle, and any Grade 4 or greater elevation in AST ALT values | . Participants were assessed every week or more often as needed during Cycle 1, and every Day 1 Cycles 2 and onward-Dose-limiting toxicities (DLTs) occurring during the first cycle of treatment will be used in determining the Phase II MTD/RP2D | 
| Number of Patients Who Had a Minimal Residual Disease (MRD) Negative Complete Response (CR) 2 Months After Chemotherapy | To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 2 months post last cycle of FCR, participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (IPI-145+ FCR) in tandem with a chest,neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. This will include all patients treated and evaluable at maximum tolerated dose, and at the recommended phase II dose ( RP2D) | 2 months after completion of combination therapy of IPI-145 and FCR | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) | At baseline, End of Cycle 3, and 2 months post FCR | 
| Number of Participants With Serious and Non-Serious Adverse Events | Toxicity assessments will be done using the CTEP Version 4.0 of the NCI Common Terminology Criteria for Adverse Events (CTCAE) and will include all participants who have received at least 1 dose of IPI-145. Toxicities will be assessed at minimum every week during cycle 1, on Day 1 of every cycle during Cycle 2 onward, and every other cycle Day 1 during maintenance. | Up to 210 days | 
| Rate of Minimal Residual Disease (MRD) in the Peripheral Blood | Participants will have MRD testing in the peripheral blood by four-color flow cytometry at the end of cycle 3, 2 months post combination therapy, and every 6 months thereafter for the duration of treatment and subsequent follow up | 2 Years | 
| Rate of Treatment Related Adverse Effects | Participants will be evaluable for this endpoint if they have had at least 1 dose of study treatment. Toxicities will be assessed at minimum each week during cycle 1, and each day 1 during combination therapy, and then every two months thereafter. CTCAE version 4.0 will be used to assess toxicity term and grading. | 210 days | 
| Determine the Association of Established CLL Prognostic Factors With Clinical Response | Fisher's exact test for categorical variables and Wilcoxon's rank sum test will be used- | 2 Years | 
| Rate of Complete Response and Partial Response | Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) | At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter | 
| Rate of Progression Free Survival | 2008 IW-CLL criteria | At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter | 
| Event Free Survival Rate | Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) | At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter | 
| Duration of Remission Rate | Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)Frequency of follow up visits and scans are per MD discretion. Recommended follow up visits for a minimum of one year | At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Lymphocytic Leukemia