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

• Sponsor: Piramal Enterprises Limited (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00843050
• Collaborator: (none)
• Enrollment: 13
• Locations: 20
• Arm: 1
• Duration (Months): 33
• Patients Per Site: 0.7
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Mantle Cell Lymphoma	Drug: P276-00	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Nov 1, 2009
• Actual Primary Completion Date: Feb 1, 2011
• Anticipated Study Completion Date: Aug 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

• 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 Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Piramal Enterprises Limited
• ClinicalTrials.gov Identifier: NCT00843050
• Other Study ID Numbers: P276-00/23/08
• First Posted: Feb 13, 2009
• Last Update Posted: Jul 27, 2012
• Last Verified: Jun 1, 2012

• Keywords provided by Piramal Enterprises Limited: CKD inhibitor; Mantle Cell Lymphoma
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell

Study Results

Participant Flow

Recruitment Details	This study was conducted across multiple centers in the United States and India.

Arm/Group Title	P276-00
Arm/Group Description	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
Period Title: Overall Study
STARTED	13
COMPLETED	0
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	P276-00
Arm/Group Description	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
Overall Participants	13
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 38.5%
>=65 years	8 61.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.8 (9.99)
Sex: Female, Male (Count of Participants)
Female	4 30.8%
Male	9 69.2%
Region of Enrollment (participants) [Number]
United States	8 61.5%
India	5 38.5%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The efficacy population includes all patients who have completed at least two cycles of P276-00 therapy and have tumor measurements.

Arm/Group Title	P276-00
Arm/Group Description	P276-00: All patients received 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 was progression of disease or unacceptable toxicity
Measure Participants	0

2. Secondary Outcome

Title	Duration of Response
Description	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 Frame	End of the study treatment

Outcome Measure Data

Analysis Population Description

The efficacy population includes all patients who have completed at least two cycles of P276-00 therapy and have tumor measurements.

Arm/Group Title	P276-00
Arm/Group Description	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
Measure Participants	0

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The efficacy population includes all patients who have completed at least two cycles of P276-00 therapy and have tumor measurements.

Arm/Group Title	P276-00
Arm/Group Description	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
Measure Participants	0

Adverse Events

Arm/Group Title	P276-00
Arm/Group Description	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
All Cause Mortality
	P276-00
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	P276-00
	Affected / at Risk (%)	# Events
Total	2/13 (15.4%)
Blood and lymphatic system disorders
Thrombocytopenia	1/13 (7.7%)	2
Cardiac disorders
Atrial fibrillation	1/13 (7.7%)	1
General disorders
Disease Progression	2/13 (15.4%)	2
Infections and infestations
Herpes Zoster	1/13 (7.7%)	1
Renal and urinary disorders
Elevated Creatinine,	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	P276-00
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Blood and lymphatic system disorders
Anaemia	3/13 (23.1%)	4
neutropenia	1/13 (7.7%)	2
Cardiac disorders
Cardiac murmur	1/13 (7.7%)	1
Electrocardiogram QT prolonged	2/13 (15.4%)	2
Hypotension	6/13 (46.2%)	10
Left atrial dilatation	1/13 (7.7%)	1
Sinus tachycardia	1/13 (7.7%)	2
Tachycardia	1/13 (7.7%)	1
Eye disorders
Dry Eye	1/13 (7.7%)	2
Gastrointestinal disorders
Abdominal distension	1/13 (7.7%)	1
Ascites	1/13 (7.7%)	1
Constipation	1/13 (7.7%)	1
Decrreased Appetite	2/13 (15.4%)	2
Diarrhoea	4/13 (30.8%)	6
Dyspepsia	2/13 (15.4%)	2
Gastritis	1/13 (7.7%)	1
nausea	1/13 (7.7%)	1
General disorders
Asthenia	1/13 (7.7%)	1
Chills	1/13 (7.7%)	1
Dehydration	1/13 (7.7%)	1
Fatigue	4/13 (30.8%)	5
Headache	2/13 (15.4%)	2
Lymphadenopathy	1/13 (7.7%)	1
nocturia	1/13 (7.7%)	1
Non-cardiac chest pain	1/13 (7.7%)	1
Oedema	2/13 (15.4%)	4
Oedema peripheral	5/13 (38.5%)	5
pain	1/13 (7.7%)	1
Pain in extremity	2/13 (15.4%)	2
Penile swelling	1/13 (7.7%)	1
Pruritus	1/13 (7.7%)	1
Rash	1/13 (7.7%)	1
Rash Pruritic	1/13 (7.7%)	1
Rash pustular	1/13 (7.7%)	1
skin burning sensation	1/13 (7.7%)	1
spleen palpable	1/13 (7.7%)	1
Infections and infestations
Arthropod bite	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Injection site reaction	1/13 (7.7%)	1
Injection site swelling	1/13 (7.7%)	1
Post operative wound complication	1/13 (7.7%)	1
Investigations
Aspartate aminotransferase increased	2/13 (15.4%)	2
Blood Alkaline Phosphatase increased	1/13 (7.7%)	1
Blood creatinine increased	1/13 (7.7%)	1
Blood lactate dehydrogenase increased	1/13 (7.7%)	1
lymphocyte count increased	1/13 (7.7%)	1
neutrophil count decreased	1/13 (7.7%)	1
Platelet count decreased	1/13 (7.7%)	1
White blood cell count decreased	1/13 (7.7%)	1
White blood cell count increased	1/13 (7.7%)	1
Metabolism and nutrition disorders
Hyperglycaemia	1/13 (7.7%)	1
hypertriglyceridemia	1/13 (7.7%)	1
Hyperuricaemia	1/13 (7.7%)	3
Hypocalcaemia	1/13 (7.7%)	1
hypokalemia	2/13 (15.4%)	2
hypomagnesaemia	1/13 (7.7%)	1
hypophosphataemia	1/13 (7.7%)	1
Pollakiuria	1/13 (7.7%)	1
Nervous system disorders
Dizziness	2/13 (15.4%)	2
Insomnia	2/13 (15.4%)	2
Panic attack	1/13 (7.7%)	1
Psychiatric disorders
Anxiety	1/13 (7.7%)	1
Renal and urinary disorders
Urinary tract infection	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/13 (15.4%)	2
hypoxia	1/13 (7.7%)	1
nasal congestion	1/13 (7.7%)	7
Pleural effusion	2/13 (15.4%)	2
Skin and subcutaneous tissue disorders
Dry Skin	2/13 (15.4%)	2
Erythema	1/13 (7.7%)	1
Petechiae	1/13 (7.7%)	2
Rosacea	1/13 (7.7%)	1
Urticaria papular	1/13 (7.7%)	1

Limitations/Caveats

The Sponsor has terminated the study based on interim results. All subjects were off study at the time of termination. There are no major safety or tolerability concerns from this study. The study results published here are preliminary results.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.