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

Single-Arm, Open-Label, Multicenter Phase II Study to Evaluate the Efficacy and Safety of P276-00 in Patients With Relapsed and/or Refractory Mantle Cell Lymphoma

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.

Study Overview

• Status: Terminated
• Conditions: Mantle Cell Lymphoma
• Intervention / Treatment: Drug: P276-00

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.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• India
  • Delhi
    • New Delhi, Delhi, India, 10029
      • Institute Rotary Cancer Hospital, All India Institute of Medical Sciences
  • Karnataka
    • Bangalore, Karnataka, India, 34
      • St. Johns Medical College & Hospital
  • Kerala
    • Calicut, Kerala, India, 16
      • Malabar Institute of Medical Sciences
  • Maharashtra
    • Mumbai, Maharashtra, India, 400 026
      • Jaslok Hospital and Research Centre
    • Mumbai, Maharashtra, India, 400012
      • Tata Memorial Hospital
    • Nagpur, Maharashtra, India, 440012
      • Cancer Care Clinic and Hospital
  • Tamil nadu
    • Madurai, Tamil nadu, India, 625107
      • Meenakshi mission hospital and research centre
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona
    • Scottsdale, Arizona, United States, 85259
      • Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Arizona
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • College of Medicine, Mayo Clinic
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research
    • Dover, Ohio, United States, 44622
      • Gabrail Cancer Center Research
  • Tennessee
    • Nashville, Tennessee, United States, 37232-5505
      • Vanderbilt University Medical Center
  • Texas
    • New Braunfels, Texas, United States, 78130
      • Cancer Care Centers of South Texas
    • San Antonio, Texas, United States, 78229
      • Cancer Care Centers of South Texas
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute, 2000 Circle of Hope, Room 2145
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance
    • Seattle, Washington, United States, 98195
      • Department of Medicine, University of Washington
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-5156
      • Dept of Hematology/Oncology, University of Wisconsin- Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Objective Response Rate	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.	End of every 2 cycles and end of the study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response	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.	End of the study treatment
Time to Progression	It is defined as the time from day 1 of the study drug administration until the first date of progressive disease.	End of study treatment

Collaborators and Investigators

• Sponsor: Piramal Enterprises Limited
• Investigators: Principal Investigator: Brad Kahl, MD, Director of the Lymphoma Service and Associate Professor of Medicine, University of Wisconsin- Madison; Principal Investigator: Gabrail Nashat, MD, CEO, President, Gabrail Cancer Center; Principal Investigator: Martha Glenn, MD, Associate Professor of Medicine, Huntsman Cancer Institute, Salt Lake City; Principal Investigator: Andre Goy, MD, Director of Lymphoma and Deputy Director of Cancer Center, Hackensack University Medical Center, Hackensack; Principal Investigator: Roger Lyons, MD, President, Cancer Care Centers of South Texas , San Antonio; Principal Investigator: Nishitha Reddy, MD, Vanderbilt University Medical Center, Nashville; Principal Investigator: Reena Nair, MD, Professor and Medical Oncologist, Tata Memorial Hospital, Mumbai, India; Principal Investigator: Anand Pathak, MD, Medical Oncologist, Cancer Care Clinic and Hospital, Nagpur, India; Principal Investigator: Vinod Raina, MD, Head Dept of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India; Principal Investigator: N K Warrier, MD, Senior Consultant Oncologist, Malabar Institute of Medical Sciences, Calicut, India; Principal Investigator: Cecil Ross, MD, Consultant Oncologist, St. Johns Medical College & Hospital, Bangalore, India; Principal Investigator: Kirushna kumar, MD, Consultant Oncologist, Meenakshi mission hospital and research centre, Madurai, India; Principal Investigator: S H Advani, MD, Consultant Oncologist, Jaslok Hospital and Research Centre, Mumbai, India; Principal Investigator: Patrick Johnston, MD, Associate Professor of Medicine, College of Medicine, Mayo Clinic, Rochester, USA; Principal Investigator: Ajay Gopal, MD, Associate Professor of Medicine, Department of Medicine, University of Washington, Seattle, Washington.; Principal Investigator: Craig Reeder, MD, Consultant, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Arizona

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): February 1, 2011
• Study Completion (Anticipated): August 1, 2012

Study Registration Dates

• First Submitted: February 12, 2009
• First Submitted That Met QC Criteria: February 12, 2009
• First Posted (Estimate): February 13, 2009

Study Record Updates

• Last Update Posted (Estimate): July 27, 2012
• Last Update Submitted That Met QC Criteria: June 20, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: Mantle Cell Lymphoma; CKD inhibitor
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Mantle-Cell
• Other Study ID Numbers: P276-00/23/08