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Clinical Study of Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Primary Purpose

Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Status
Suspended
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
P1446A-05
Sponsored by
Piramal Enterprises Limited
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients must have histologically or flow cytometry confirmed diagnosis of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) according to the IWCLL 2008 criteria. The malignant B cells must co-express CD5 with CD19 or CD20. Patients who lack CD23 expression on their leukemia cells should be examined for (and found NOT to have) either t(11;14) or cyclin D1 overexpression, to rule out mantle cell lymphoma.
  2. Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring treatment:

    • A minimum of any one of the following constitutional symptoms:

    Unintentional weight loss >10% within the previous 6 months prior to screening Extreme fatigue (unable to work or perform usual activities) Fevers of greater than 100.5ᵒF for ≥2 weeks without evidence of infection Night sweats without evidence of infection.

    • Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia or thrombocytopenia
    • Massive (i.e., >6 cm below the left costal margin), progressive or symptomatic splenomegaly
    • Massive nodes or clusters (i.e., >10 cm in longest diameter) or progressive lymphadenopathy
    • Progressive lymphocytosis with an increase of >50% over a 2-month period, or an anticipated doubling time of less than 6 months
    • Autoimmune anemia or thrombocytopenia that is poorly responsive to corticosteroids
  3. Patients with relapsed/refractory CLL defined as having received ≥2 treatment regimens that included:

    • A treatment regimen containing cytotoxic agents (eg, fludarabine, pentostatin, cladribine, cyclophosphamide, chlorambucil, bendamustine) AND
    • A treatment regimen containing a therapeutic anti-CD20 antibody (e.g., rituximab, ofatumumab, obinutuzumab) AND
    • A treatment regimen containing ibrutinib unless patient is not a candidate
    • All treatment regimens must have been administered for ≥2 cycles unless patient is immediately allergic or intolerant to the regimen
    • A disease expert at the study site must have a detailed discussion with the patient of other treatment options which either have been approved by the FDA or are part of or relevant to the standard care of patients with B-CLL/SLL in the multiply relapsed setting
  4. Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  5. Patients ≥18 year old
  6. Patients must have organ function as defined below:

    • Direct bilirubin ≤2 X institutional ULN (unless due to known Gilbert's syndrome or compensated hemolysis directly attributable to CLL)
    • AST or ALT less than or equal to 2.5 X institutional ULN
    • Creatinine ≤1.5 mg/dL OR estimated creatinine clearance ≥60 mL/min calculated using Cockcroft-Gault equation
    • Total white blood cell count ≤200,000/mm3
    • Platelets ≥10,000/mm3 with no active bleeding
  7. Ability to understand and the willingness to sign a written informed consent document
  8. Ability to swallow and retain oral medication
  9. Patients receiving chronic or acute warfarin treatment are not excluded, but should be monitored very closely or considered for switch to other therapies. P1446A-05 is both highly protein bound and a competitive inhibitor of CYP2C9 at higher concentrations and thus may potentiate the action of warfarin in patients
  10. Women of childbearing potential must have a negative serum β-human chorionic gonadotropin or urine pregnancy test at screening
  11. All patients of reproductive potential (heterosexually active men and women) must agree to a use of a barrier method of contraception and a second method of contraception and men must agree not to donate sperm during the study and for at least 4 weeks after receiving the last dose of study treatment

Exclusion Criteria:

  1. Recent therapeutic intervention including a) prior nitrosoureas or mitomycin C; prior radio- or toxin-immunoconjugates within 6 weeks; b) therapeutic anticancer antibodies (including rituximab, ofatumumab and obinituzumab) within 4 weeks; and c) all other chemotherapy or radiation therapy within 2 weeks prior to initiation of study drug
  2. The patient has not recovered from adverse events related to prior therapy to Grade ≤1 (excluding Grade 2 alopecia and neuropathy)
  3. Chronic use of corticosteroids in excess of prednisone 20 mg/day or its equivalent
  4. Patients who have been in the past enrolled on a study of a Cdk inhibitor
  5. History of prior malignancy except: a) Malignancy treated with curative intent and no known active disease present for ≥2 years prior to initiation of current study; b) adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; c) adequately treated in situ carcinomas (e.g., cervical, esophageal, breast, etc.) without evidence of disease; d) asymptomatic prostate cancer managed with "watch and wait" strategy; e) myelodysplastic syndrome which is clinically well controlled and no evidence of the cytogenetic abnormalities characteristic of myelodysplasia on the bone marrow at screening
  6. Patients with uncontrolled immune hemolysis or thrombocytopenia (positive direct antiglobulin test in absence of hemolysis is not an exclusion)
  7. Patients with known Richter's transformation which is progressive and is deemed to require immediate chemotherapy (history of Richter's transformation is not an exclusion); patients with prolymphocytic leukemia (prolymphocytes in blood >55%)
  8. Patients with clinically significant medical condition of malabsorption, inflammatory bowel disease, chronic conditions which manifest with diarrhea, refractory nausea, vomiting or any other condition that will interfere significantly with the absorption of study drugs
  9. Patients with mean QTc interval >450 msec at screening and patients taking drugs known to prolong the QTc interval (see Section 9, Appendix D) who cannot be switched to an alternative drug
  10. Nursing woman
  11. Known history of Human Immunodeficiency Virus (HIV) or active Hepatitis B or C. Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, but should have hepatitis serologies and Hepatitis B DNA monitored periodically by the treating physician.
  12. Any condition for which participation in the study is judged by the Investigator to be detrimental to the patient with inter-current illness including, but not limited to an uncontrolled active infection; unstable angina pectoris; uncontrolled cardiac arrhythmia; transient ischemic attack or pulmonary embolism during the previous 1 month or psychiatric/social situations that would jeopardize compliance with study requirements.

Sites / Locations

  • Dana-Farber Cancer Institute
  • Dartmouth-Hitchcock Norris Cotton Cancer Centre

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

P1446A-05

Arm Description

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose
To establish maximum tolerated dose (MTD) of P1446A 05 in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). There will be two phase, a dose escalation phase, followed by a dose extension phase. In the 'dose extension phase', up to a total of 14 patients will be treated at the MTD of P1446A-05, determined in the 'dose escalation' phase, until the occurrence of disease progression or unacceptable toxicity or death
Dose Limiting Toxicity
To establish dose limiting toxicities (DLTs) of P1446A 05 in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). - There will be two phase, a dose escalation phase, followed by a dose extension phase.

Secondary Outcome Measures

Overall response
To determine the efficacy (overall response ) of P1446A 05 in patients with relapsed/refractory CLL. Overall Response will be assessed according to IWCLL 2008 criteria. Kaplan-Meier curve of overall survival will also be presented. OS will be evaluated in the dose extension phase only.
Progression-free survival
To determine the efficacy (progression-free survival) of P1446A 05 in patients with relapsed/refractory CLL. Kaplan-Meier estimates of progression-free survival i.e. median and inter-quartile range will be presented. Kaplan-Meier curve of overall survival will also be presented. OS will be evaluated in the dose extension phase only.
Pharmacokinetic profile (Cmax,Tmax and AUC)
Samples for pharmacokinetic analysis for PK profile (Cmax,Tmax and AUC) will be collected on S-D1at pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h post on Day S-D1 of single dose period (for Dose Levels 1, 2 and 3). In the continuous dose period, samples will be collected on Day 28 of Cycle 1 at pre-dose, and at 0.5, 2, 4, 6, 8 and 24 h post-dose. Additional samples will be collected pre dose on Day 15 and 22 of Cycle 1 to monitor the attainment of steady state. Pre-dose samples will also be collected on C2D15, C2D28, C3D15, C3D28 and C5D1. PK parameters will be obtained using standard non-compartmental methods. PK evaluations will not be performed in the dose extension phase. Descriptive statistics will be provided for the PK parameters. The PK analysis will be performed using WinNonlin software

Full Information

First Posted
April 8, 2014
Last Updated
September 2, 2014
Sponsor
Piramal Enterprises Limited
Collaborators
Dana-Farber Cancer Institute, Norris Cotton Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT02117336
Brief Title
Clinical Study of Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)
Official Title
A Phase I/Ib Study of P1446A-05 in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).
Study Type
Interventional

2. Study Status

Record Verification Date
September 2014
Overall Recruitment Status
Suspended
Why Stopped
Sponsor decision not related to patient safety
Study Start Date
June 2014 (undefined)
Primary Completion Date
October 2016 (Anticipated)
Study Completion Date
March 2017 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Piramal Enterprises Limited
Collaborators
Dana-Farber Cancer Institute, Norris Cotton Cancer Center

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This is an open-label, Phase I/Ib trial with a dose escalation phase, followed by a dose extension phase. The objective of the dose escalation phase is to evaluate the pharmacokinetics (PK) and MTD of P1446A-05 in relapsed/refractory CLL and the objective of the dose extension phase is to evaluate the safety, efficacy and pharmacodynamics of P1446A-05 in 14 patients at the MTD level.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
P1446A-05
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
P1446A-05
Intervention Description
The study have dose escalation phase, followed by a dose extension phase. Dose escalation phase: five Dose Levels will be evaluated in the 'dose escalation' phase. The Dose Levels selected are 50 mg (Dose Level 1), 75 mg (Dose Level 2), 125 mg (Dose Level 3), 200 mg (Dose Level 4) and 275 mg (Dose Level 5), once daily. If required, a 25 mg once daily dose (Dose Level -1) will also be studied. For Dose Levels 1, 2 and 3 there will be 2- dosing periods: Single Dose and Continuous Dose. At least 3-patients will be enrolled at each Dose Level. Dosing regimens planned for Dose Level 4 and 5 are 200 and 275 mg once daily. In the continuous dose period, patients will receive P1446A-05 on a 28-day cycle, until the occurrence of disease progression or unacceptable toxicity. Dose Extension Phase: Up to a total of 14 patients will be treated at the MTD of P1446A-05, determined in the dose escalation phase, until the occurrence of disease progression or unacceptable toxicity or death.
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose
Description
To establish maximum tolerated dose (MTD) of P1446A 05 in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). There will be two phase, a dose escalation phase, followed by a dose extension phase. In the 'dose extension phase', up to a total of 14 patients will be treated at the MTD of P1446A-05, determined in the 'dose escalation' phase, until the occurrence of disease progression or unacceptable toxicity or death
Time Frame
Cycle 1 (Day 1 to 28 )
Title
Dose Limiting Toxicity
Description
To establish dose limiting toxicities (DLTs) of P1446A 05 in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). - There will be two phase, a dose escalation phase, followed by a dose extension phase.
Time Frame
Cycle 1 (Day 1 to 28 )
Secondary Outcome Measure Information:
Title
Overall response
Description
To determine the efficacy (overall response ) of P1446A 05 in patients with relapsed/refractory CLL. Overall Response will be assessed according to IWCLL 2008 criteria. Kaplan-Meier curve of overall survival will also be presented. OS will be evaluated in the dose extension phase only.
Time Frame
At the end of every 2 cycles,Until disease progression or unacceptable toxicity (average of 2years)
Title
Progression-free survival
Description
To determine the efficacy (progression-free survival) of P1446A 05 in patients with relapsed/refractory CLL. Kaplan-Meier estimates of progression-free survival i.e. median and inter-quartile range will be presented. Kaplan-Meier curve of overall survival will also be presented. OS will be evaluated in the dose extension phase only.
Time Frame
At the end of every 2 cycles, until disease progression or unacceptable toxicity (average of 2years)
Title
Pharmacokinetic profile (Cmax,Tmax and AUC)
Description
Samples for pharmacokinetic analysis for PK profile (Cmax,Tmax and AUC) will be collected on S-D1at pre-dose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h post on Day S-D1 of single dose period (for Dose Levels 1, 2 and 3). In the continuous dose period, samples will be collected on Day 28 of Cycle 1 at pre-dose, and at 0.5, 2, 4, 6, 8 and 24 h post-dose. Additional samples will be collected pre dose on Day 15 and 22 of Cycle 1 to monitor the attainment of steady state. Pre-dose samples will also be collected on C2D15, C2D28, C3D15, C3D28 and C5D1. PK parameters will be obtained using standard non-compartmental methods. PK evaluations will not be performed in the dose extension phase. Descriptive statistics will be provided for the PK parameters. The PK analysis will be performed using WinNonlin software
Time Frame
SD1, Cycle1-Cycle 5 (average of 5 month)
Other Pre-specified Outcome Measures:
Title
Biomarker Analysis
Description
To assess whether established (IGHV, p53 and Notch mutational status and ZAP70 and CD38 expression,) and exploratory biomarkers (e.g. expression levels of Cyclin D1, p53 etc.) predict response to P1446A-05 in relapsed/refractory CLL
Time Frame
Cycle1Day1, Cycle1Day28, Until disease progression or unacceptable toxicity (average of 2years)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have histologically or flow cytometry confirmed diagnosis of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) according to the IWCLL 2008 criteria. The malignant B cells must co-express CD5 with CD19 or CD20. Patients who lack CD23 expression on their leukemia cells should be examined for (and found NOT to have) either t(11;14) or cyclin D1 overexpression, to rule out mantle cell lymphoma. Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring treatment: A minimum of any one of the following constitutional symptoms: Unintentional weight loss >10% within the previous 6 months prior to screening Extreme fatigue (unable to work or perform usual activities) Fevers of greater than 100.5ᵒF for ≥2 weeks without evidence of infection Night sweats without evidence of infection. Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia or thrombocytopenia Massive (i.e., >6 cm below the left costal margin), progressive or symptomatic splenomegaly Massive nodes or clusters (i.e., >10 cm in longest diameter) or progressive lymphadenopathy Progressive lymphocytosis with an increase of >50% over a 2-month period, or an anticipated doubling time of less than 6 months Autoimmune anemia or thrombocytopenia that is poorly responsive to corticosteroids Patients with relapsed/refractory CLL defined as having received ≥2 treatment regimens that included: A treatment regimen containing cytotoxic agents (eg, fludarabine, pentostatin, cladribine, cyclophosphamide, chlorambucil, bendamustine) AND A treatment regimen containing a therapeutic anti-CD20 antibody (e.g., rituximab, ofatumumab, obinutuzumab) AND A treatment regimen containing ibrutinib unless patient is not a candidate All treatment regimens must have been administered for ≥2 cycles unless patient is immediately allergic or intolerant to the regimen A disease expert at the study site must have a detailed discussion with the patient of other treatment options which either have been approved by the FDA or are part of or relevant to the standard care of patients with B-CLL/SLL in the multiply relapsed setting Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Patients ≥18 year old Patients must have organ function as defined below: Direct bilirubin ≤2 X institutional ULN (unless due to known Gilbert's syndrome or compensated hemolysis directly attributable to CLL) AST or ALT less than or equal to 2.5 X institutional ULN Creatinine ≤1.5 mg/dL OR estimated creatinine clearance ≥60 mL/min calculated using Cockcroft-Gault equation Total white blood cell count ≤200,000/mm3 Platelets ≥10,000/mm3 with no active bleeding Ability to understand and the willingness to sign a written informed consent document Ability to swallow and retain oral medication Patients receiving chronic or acute warfarin treatment are not excluded, but should be monitored very closely or considered for switch to other therapies. P1446A-05 is both highly protein bound and a competitive inhibitor of CYP2C9 at higher concentrations and thus may potentiate the action of warfarin in patients Women of childbearing potential must have a negative serum β-human chorionic gonadotropin or urine pregnancy test at screening All patients of reproductive potential (heterosexually active men and women) must agree to a use of a barrier method of contraception and a second method of contraception and men must agree not to donate sperm during the study and for at least 4 weeks after receiving the last dose of study treatment Exclusion Criteria: Recent therapeutic intervention including a) prior nitrosoureas or mitomycin C; prior radio- or toxin-immunoconjugates within 6 weeks; b) therapeutic anticancer antibodies (including rituximab, ofatumumab and obinituzumab) within 4 weeks; and c) all other chemotherapy or radiation therapy within 2 weeks prior to initiation of study drug The patient has not recovered from adverse events related to prior therapy to Grade ≤1 (excluding Grade 2 alopecia and neuropathy) Chronic use of corticosteroids in excess of prednisone 20 mg/day or its equivalent Patients who have been in the past enrolled on a study of a Cdk inhibitor History of prior malignancy except: a) Malignancy treated with curative intent and no known active disease present for ≥2 years prior to initiation of current study; b) adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; c) adequately treated in situ carcinomas (e.g., cervical, esophageal, breast, etc.) without evidence of disease; d) asymptomatic prostate cancer managed with "watch and wait" strategy; e) myelodysplastic syndrome which is clinically well controlled and no evidence of the cytogenetic abnormalities characteristic of myelodysplasia on the bone marrow at screening Patients with uncontrolled immune hemolysis or thrombocytopenia (positive direct antiglobulin test in absence of hemolysis is not an exclusion) Patients with known Richter's transformation which is progressive and is deemed to require immediate chemotherapy (history of Richter's transformation is not an exclusion); patients with prolymphocytic leukemia (prolymphocytes in blood >55%) Patients with clinically significant medical condition of malabsorption, inflammatory bowel disease, chronic conditions which manifest with diarrhea, refractory nausea, vomiting or any other condition that will interfere significantly with the absorption of study drugs Patients with mean QTc interval >450 msec at screening and patients taking drugs known to prolong the QTc interval (see Section 9, Appendix D) who cannot be switched to an alternative drug Nursing woman Known history of Human Immunodeficiency Virus (HIV) or active Hepatitis B or C. Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, but should have hepatitis serologies and Hepatitis B DNA monitored periodically by the treating physician. Any condition for which participation in the study is judged by the Investigator to be detrimental to the patient with inter-current illness including, but not limited to an uncontrolled active infection; unstable angina pectoris; uncontrolled cardiac arrhythmia; transient ischemic attack or pulmonary embolism during the previous 1 month or psychiatric/social situations that would jeopardize compliance with study requirements.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dr Alexey V Danilov, MD, PhD
Organizational Affiliation
Dartmouth-Hitchcock Norris Cotton Cancer Centre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Dr Jennifer R Brown, MD, PhD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Dartmouth-Hitchcock Norris Cotton Cancer Centre
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States

12. IPD Sharing Statement

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Clinical Study of Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

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