Chronic Lymphocytic Leukemia
Conditions
Keywords
Chronic Lymphocytic Leukemia
Brief summary
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
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.
Interventions
DRUGIPI-145
oral PI3K delta/gamma inhibitor
DRUGFludarabine
intravenous chemotherapy
DRUGCyclophosphamide
intravenous chemotherapy
DRUGRituximab
intravenous immunotherapy
Sponsors
Dana-Farber Cancer Institute
Secura Bio, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) During Phase I | . 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 | 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 |
| Number of Patients Who Had a Minimal Residual Disease (MRD) Negative Complete Response (CR) 2 Months After Chemotherapy | 2 months after completion of combination therapy of IPI-145 and FCR | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious and Non-Serious Adverse Events | Up to 210 days | 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. |
| Rate of Minimal Residual Disease (MRD) in the Peripheral Blood | 2 Years | 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 |
| Rate of Treatment Related Adverse Effects | 210 days | 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. |
| Determine the Association of Established CLL Prognostic Factors With Clinical Response | 2 Years | Fisher's exact test for categorical variables and Wilcoxon's rank sum test will be used- |
| Rate of Complete Response and Partial Response | At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter | Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) |
| Event Free Survival Rate | At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter | Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) |
| Rate of Progression Free Survival | At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter | 2008 IW-CLL criteria |
| Duration of Remission Rate | At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter | 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 |
| Overall Response Rate | At baseline, End of Cycle 3, and 2 months post FCR | Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMatthew Davids, MD
Dana-Farber Cancer Institute
Participant flow
Recruitment details
Participants in the Phase I portion of the study enrolled in outpatient clinic setting from 6/27/2014 to 1/13/2015 and to the Phase II study from 4/14/2015 to 8/15/2016
Participants by arm
| Arm | Count |
|---|---|
| Phase I Cohort 1: IPI-145 25mg Once Daily + FCR Phase I Cohort 1 patients received oral agent IPI-145 25mg daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. | 6 |
| Phase I Cohort 2: IPI-145 25mg Once Daily Phase I Cohort 2 patients received oral agent IPI-145 25mg twice BID) daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. | 6 |
| Phase II Dose Expansion ( MTD): IPI 145 25mg BID Phase II (MTD) CLL participants received the regimen established in the Phase I study ( January 2015). Phase II Participants received oral IPI-145 25mg twice daily (BID) for up to 6 cycles of combination therapy and 2 years of maintenance ( monotherapy) and received standard dosing if Fludarabine, Cyclophosphamide, and Rituxan (FCR) on days 1-3 of each cycle for up to 6 cycles. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. | 20 |
| Total | 32 |
Baseline characteristics
| Characteristic | Phase II Dose Expansion ( MTD): IPI 145 25mg BID | Total | Phase I Cohort 1: IPI-145 25mg Once Daily + FCR | Phase I Cohort 2: IPI-145 25mg Once Daily |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 31 Participants | 6 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 28 Participants | 6 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 30 Participants | 6 Participants | 6 Participants |
| Region of Enrollment United States | 20 participants | 32 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 6 Participants | 10 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 14 Participants | 22 Participants | 5 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 20 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 20 / 20 |
| serious Total, serious adverse events | 6 / 6 | 6 / 6 | 20 / 20 |
Outcome results
Primary
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
Time frame: . 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
Population: Patients who have received no prior therapy for CLL but who meet IW-CLL 2008 Criteria for requiring treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Cohort 1: IPI-145 25mg Once Daily + FCR | Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) During Phase I | 2 Participants |
| Phase I Cohort 2 (MTD): IPI-145 25mg Twice Daily + FCR | Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) During Phase I | 1 Participants |
Primary
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)
Time frame: 2 months after completion of combination therapy of IPI-145 and FCR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Cohort 1: IPI-145 25mg Once Daily + FCR | Number of Patients Who Had a Minimal Residual Disease (MRD) Negative Complete Response (CR) 2 Months After Chemotherapy | 23 Percentage of participants |
Secondary
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-
Time frame: 2 Years
Secondary
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
Time frame: At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter
Secondary
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)
Time frame: At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter
Secondary
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.
Time frame: Up to 210 days
Secondary
Overall Response Rate
Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)
Time frame: At baseline, End of Cycle 3, and 2 months post FCR
Secondary
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)
Time frame: At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter
Secondary
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
Time frame: 2 Years
Secondary
Rate of Progression Free Survival
2008 IW-CLL criteria
Time frame: At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter
Secondary
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.
Time frame: 210 days