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

NCT02117336 | Suspended Phase 1

• 1 other identifier: P1446A-05/79/13
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 2

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.

Conditions

Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Outcome Measures

Primary Outcomes (2)

• 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

  Cycle 1 (Day 1 to 28 )

• 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.

  Cycle 1 (Day 1 to 28 )

Secondary Outcomes (3)

• Overall response

  At the end of every 2 cycles,Until disease progression or unacceptable toxicity (average of 2years)

• Progression-free survival

  At the end of every 2 cycles, until disease progression or unacceptable toxicity (average of 2years)

• Pharmacokinetic profile (Cmax,Tmax and AUC)

  SD1, Cycle1-Cycle 5 (average of 5 month)

Other Outcomes (1)

• Biomarker Analysis

  Cycle1Day1, Cycle1Day28, Until disease progression or unacceptable toxicity (average of 2years)

Study Arms (1)

P1446A-05

EXPERIMENTAL

Drug: P1446A-05

Interventions

P1446A-05 DRUG

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.

P1446A-05

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• Piramal Enterprises Limited: lead
• Dana-Farber Cancer Institute: collaborator
• Norris Cotton Cancer Center: collaborator

Study Sites (2)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Dartmouth-Hitchcock Norris Cotton Cancer Centre

Lebanon, New Hampshire, 03756, United States

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Dr Alexey V Danilov, MD, PhD

  Dartmouth-Hitchcock Norris Cotton Cancer Centre

  PRINCIPAL INVESTIGATOR

• Dr Jennifer R Brown, MD, PhD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 8, 2014
• First Posted: April 17, 2014
• Study Start: June 1, 2014
• Primary Completion: October 1, 2016
• Study Completion: March 1, 2017
• Last Updated: September 3, 2014

Record last verified: 2014-09

Locations

US (2)