A Phase II Study to Evaluate Efficacy and Safety of P276-00 in Relapsed and/or Refractory Mantle Cell Lymphoma

Phase 2

Terminated

Conditions: Mantle Cell Lymphoma

Interventions: Drug: P276-00

Registration Number: NCT00843050

Lead Sponsor: Piramal Enterprises Limited

Brief Summary: The purpose of this study is to determine whether P276-00 is safe and effective in treatment of Mantle Cell Lymphoma that is recurred after or not responding to at least one previous line of treatment.

Detailed Description: Despite response rates of up to 97% with first-line standard or high-intensity chemotherapy, with or without stem-cell transplantation, most patients of mantle cell lymphoma (MCL)relapse.Prognosis of MCL after first relapse is very poor with median survival of around 1 to 2 years. Therefore, novel therapies are required for relapsed and/or refractory MCL.Overexpression of Cyclin D1 as a result of t(11;14)(q13;q32) translocation is the hallmark of MCL.It is postulated that Cyclin D1 may also have an oncogenic role independent of pRb in MCL.Therefore, inhibition of Cdk4-Cyclin D1 is a potentially promising target in MCL. P276-00 is a potent Cdk4-Cyclin D1 inhibitor worth exploring for its efficacy in MCL. Hence, this Phase II study is planned to examine the efficacy and safety of P276-00 in the treatment of patients with relapsed and/or refractory MCL.

This is an open-label, single-arm, 2-stage trial. Approximately 35 patients are planned to be enrolled into the study to obtain a total of 25 efficacy evaluable patients (patients who complete at least 2 cycles of study treatment and have tumor measurements at the end of 2 cycles). A total of 15 efficacy evaluable patients are planned to be treated in Stage I of the study. If ≥1 response (CR or PR) of any duration or ≥2 stable disease (SD) for ≥4 cycles are seen in the Stage I, then the study will continue into Stage II, in which additional patients will be treated until there are 10 additional efficacy evaluable patients.The study is divided into 3 periods: Screening, Treatment, and Follow-up. During the Screening Period, patients will provide written informed consent and be evaluated for inclusion and exclusion criteria. During the Treatment Period, patients will be administered P276-00 as intravenous (iv) infusion on Days 1 to 5 of each 21-day cycle for a minimum of 6 cycles and a maximum of 12 cycles, or until progressive disease (PD) or unacceptable toxicity occurs. Safety and efficacy evaluations will be done on Days 1 to 5 and 11 of each cycle, and on Day 21 of every 2 cycles. Pharmacokinetic (PK) assessments will be done on Cycle 1, Day 1 (pre-dose and post-dose time points), and optional biomarker assessments will be done pre-dose within 4 weeks of Day 1 and post-dose on Day 4 or 5. The End-of-Last-Cycle Visit will occur at the end of Cycle 6, or if the patient continues study treatment beyond Cycle 6, it will occur at the end of the patient's last cycle; if the patient discontinues early, these assessments will be done as an Early Exit Visit. The Follow-up Visit will occur 4 weeks (±1 week) after the End-of-Last-Cycle Visit (or Early Exit Visit) for final safety assessments.Objective response rate is the primary end point for this study. Response evaluation will be performed using the International Working Group (IWG) revised response criteria for malignant lymphoma.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 13

Inclusion Criteria

Age ≥18 years
Histological diagnosis of MCL and presence of either nuclear Cyclin D1 positivity by immunohistochemistry or t(11;14) by fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), or conventional karyotyping
Documented progression or relapse after at least 1 line of prior chemotherapy
Presence of measurable disease
ECOG performance status 0, 1, or 2
Life expectancy of at least 3 months
Ability to understand and the willingness to sign a written informed consent document (ICD)
Full recovery from all prior treatment toxicities of Common Terminology Criteria for Adverse Events (CTCAE) Grade ≤ 1

Exclusion Criteria

Prior radiation therapy, chemotherapy or biologic/targeted anticancer agents within 4 weeks of study drug administration
Prior treatment with monoclonal antibodies or any radio- or toxin- immunoconjugates within 3 months of study drug administration; however, a patient who has had rituximab treatment within 3 months and has had PD after such treatment is allowed in the study.
Prior allogeneic stem cell transplantation within 1 year of study drug administration
Current or prior CNS lymphoma
QTc > 450 msec
Unstable angina, myocardial infarction, CHF or stroke within previous 6 months of study drug administration
Presence of active and serious comorbidity and uncontrolled illness other than MCL
History of other prior malignancies except for properly treated basal cell or squamous cell carcinoma of skin, in situ cervical cancer, in situ breast cancer or early stage prostate cancer
Hemoglobin <8.0 gm/dL
Absolute neutrophil count <1000/mm3
Platelet count <50,000/mm3
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >3 × institutional upper limit of normal (ULN) (> 5 × institutional ULN if liver is involved with lymphoma or if patient has Gilbert's Disease)
Total bilirubin, >1.5 × institutional ULN (> 3 × institutional ULN if liver is involved with lymphoma or if patient has Gilbert's Disease)
Serum creatinine >1.5 × institutional ULN
Patients known to be suffering from infection with human immunodeficiency virus (HIV), tuberculosis, Hepatitis C or Hepatitis B
Pregnant or lactating women
Women of childbearing potential or men not willing to use at least 2 approved methods of contraception (one of which being a barrier method) after signing the ICD, during the entire study and for at least 4 weeks following withdrawal from the study

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
P276-00	P276-00	P276-00: All patients will receive P276-00 185 mg/m2/day as intravenous infusion over 30 minutes in 200 ml of 5% dextrose from day 1 to day 5 in each 21 days cycle for minimum 6 and maximum 12 cycles or until there is progression of disease or unacceptable toxicity

Primary Outcome Measures

Name	Time	Method
Best Overall Objective Response Rate	End of every 2 cycles and end of the study treatment	The primary efficacy endpoint is the proportion of subjects achieving an objective response. The proportion of patients achieving an objective response is the best overall objective response rate.

Secondary Outcome Measures

Name	Time	Method
Duration of Response	End of the study treatment	It is defined as the time from when the measurement criteria are met for complete or partial response until the first date that recurrent or progressive disease is objectively or clinically documented.
Time to Progression	End of study treatment	It is defined as the time from day 1 of the study drug administration until the first date of progressive disease.

Trial Locations

Locations (18): Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Arizona
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Scottsdale, Arizona, United States
Hackensack University Medical Center
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Hackensack, New Jersey, United States
Malabar Institute of Medical Sciences
🇮🇳
Calicut, Kerala, India
Jaslok Hospital and Research Centre
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Mumbai, Maharashtra, India
Tata Memorial Hospital
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Mumbai, Maharashtra, India
Institute Rotary Cancer Hospital, All India Institute of Medical Sciences
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New Delhi, Delhi, India
Meenakshi mission hospital and research centre
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Madurai, Tamil nadu, India
Vanderbilt University Medical Center
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Nashville, Tennessee, United States
Seattle Cancer Care Alliance
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Seattle, Washington, United States
College of Medicine, Mayo Clinic
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Rochester, Minnesota, United States
St. Johns Medical College & Hospital
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Bangalore, Karnataka, India
Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona
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Phoenix, Arizona, United States
Dept of Hematology/Oncology, University of Wisconsin- Madison
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Madison, Wisconsin, United States
Cancer Care Centers of South Texas
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San Antonio, Texas, United States
Department of Medicine, University of Washington
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Seattle, Washington, United States
Gabrail Cancer Center Research
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Dover, Ohio, United States
Huntsman Cancer Institute, 2000 Circle of Hope, Room 2145
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Salt Lake City, Utah, United States
Cancer Care Clinic and Hospital
🇮🇳
Nagpur, Maharashtra, India