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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

Phase 2
18 Years
Not Enrolling
Mantle Cell Lymphoma

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Trial Information

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

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.

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

- 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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Best Overall Objective Response Rate

Outcome Description:

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.

Outcome Time Frame:

End of every 2 cycles and end of the study treatment

Safety Issue:


Principal Investigator

Brad Kahl, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Director of the Lymphoma Service and Associate Professor of Medicine, University of Wisconsin- Madison


United States: Food and Drug Administration

Study ID:




Start Date:

November 2009

Completion Date:

August 2012

Related Keywords:

  • Mantle Cell Lymphoma
  • CKD inhibitor
  • Mantle Cell Lymphoma
  • Lymphoma
  • Lymphoma, Mantle-Cell



Hackensack University Medical Center Hackensack, New Jersey  07601
Vanderbilt University Medical Center Nashville, Tennessee  37232-2516
Seattle Cancer Care Alliance Seattle, Washington  98109
Cancer Care Centers of South Texas San Antonio, Texas  78229
Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona Phoenix, Arizona  85054
Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Arizona Scottsdale, Arizona  85259
College of Medicine, Mayo Clinic Rochester, Minnesota  55905
Gabrail Cancer Center Research Canton, Ohio  44718
Huntsman Cancer Institute, 2000 Circle of Hope, Room 2145 Salt Lake City, Utah  84112
Department of Medicine, University of Washington Seattle, Washington  98195
Dept of Hematology/Oncology, University of Wisconsin- Madison Madison, Wisconsin  53792-5156