Clinical trial NCT00843050: A Phase II Study to Evaluate Efficacy and Safety of P276-00 in Relapsed and/or Refractory Mantle Cell Lymphoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Mantle Cell Lymphoma
Keywords: CKD inhibitor
Mantle Cell Lymphoma
Lead sponsor: Piramal Enterprises Limited
Sponsor class: INDUSTRY
First posted: 2009-02-13
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Best Overall Objective Response Rate
timeFrame: End of every 2 cycles and end of the study treatment
Secondary outcomes:
measure: Duration of Response
timeFrame: End of the study treatment
measure: Time to Progression
timeFrame: End of study treatment
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona
state: Arizona
city: Scottsdale
country: United States
facility: Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Arizona
state: Arizona
city: Rochester
country: United States
facility: College of Medicine, Mayo Clinic
state: Minnesota
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Canton
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: Dover
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: New Braunfels
country: United States
facility: Cancer Care Centers of South Texas
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Centers of South Texas
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute, 2000 Circle of Hope, Room 2145
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Seattle
country: United States
facility: Department of Medicine, University of Washington
state: Washington
city: Madison
country: United States
facility: Dept of Hematology/Oncology, University of Wisconsin- Madison
state: Wisconsin
city: New Delhi
country: India
facility: Institute Rotary Cancer Hospital, All India Institute of Medical Sciences
state: Delhi
city: Bangalore
country: India
facility: St. Johns Medical College & Hospital
state: Karnataka
city: Calicut
country: India
facility: Malabar Institute of Medical Sciences
state: Kerala
city: Mumbai
country: India
facility: Jaslok Hospital and Research Centre
state: Maharashtra
city: Mumbai
country: India
facility: Tata Memorial Hospital
state: Maharashtra
city: Nagpur
country: India
facility: Cancer Care Clinic and Hospital
state: Maharashtra
city: Madurai
country: India
facility: Meenakshi mission hospital and research centre
state: Tamil nadu
Study officials:
affiliation: Director of the Lymphoma Service and Associate Professor of Medicine, University of Wisconsin- Madison
name: Brad Kahl, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CEO, President, Gabrail Cancer Center
name: Gabrail Nashat, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Associate Professor of Medicine, Huntsman Cancer Institute, Salt Lake City
name: Martha Glenn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Director of Lymphoma and Deputy Director of Cancer Center, Hackensack University Medical Center, Hackensack
name: Andre Goy, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: President, Cancer Care Centers of South Texas , San Antonio
name: Roger Lyons, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University Medical Center, Nashville
name: Nishitha Reddy, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Professor and Medical Oncologist, Tata Memorial Hospital, Mumbai, India
name: Reena Nair, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical Oncologist, Cancer Care Clinic and Hospital, Nagpur, India
name: Anand Pathak, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Head Dept of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
name: Vinod Raina, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Senior Consultant Oncologist, Malabar Institute of Medical Sciences, Calicut, India
name: N K Warrier, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Consultant Oncologist, St. Johns Medical College & Hospital, Bangalore, India
name: Cecil Ross, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Consultant Oncologist, Meenakshi mission hospital and research centre, Madurai, India
name: Kirushna kumar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Consultant Oncologist, Jaslok Hospital and Research Centre, Mumbai, India
name: S H Advani, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Associate Professor of Medicine, College of Medicine, Mayo Clinic, Rochester, USA
name: Patrick Johnston, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Associate Professor of Medicine, Department of Medicine, University of Washington, Seattle, Washington.
name: Ajay Gopal, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Consultant, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Arizona
name: Craig Reeder, MD
role: PRINCIPAL_INVESTIGATOR
References: