Trial of PD 0332991 Plus Bortezomib in Patients With Relapsed Mantle Cell Lymphoma
Mantle Cell Lymphoma
Conditions: official terms
Lymphoma - Lymphoma, Mantle-Cell
Study Type
Study Phase
Phase 1
Study Design
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Name: PD 0332991 Type: Drug
Name: bortezomib Type: Drug
Overall Status
Mantle cell lymphoma (MCL) is characterized by cell cycle dysregulation. PD 0332991 is a cyclin-dependent kinase 4 and 6 inhibitor capable of inhibiting cell cycling of MCL. A phase I study has demonstrated the safety and anti-lymphoma activity of PD 0332991. Bortezomib is a first generation proteasome inhibitor approved for treatment of patients with recurrent MCL. Preclinical data suggests that PD 0332991 and bortezomib may act synergistically in MCL.

PD 0332991 will be administered continuously for 12 days followed by a 9 day period without treatment. Bortezomib will be administered by intravenous bolus on days 8, 11, 15, and 18 of each cycle. One cycle is defined as three weeks. A maximum of ten cycles will be administered.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: Inclusion Criteria:

- Patients must have histologically or cytologically confirmed mantle cell lymphoma as defined by the World Health Organization. All patients must have either a demonstrated t(11;14) by karyotype, fluorescent in-situ hybridization (FISH) or positive immunohistochemistry for cyclin D1.

- Subjects must have measurable disease, defined as at least one tumor mass of > 1.5 cm in diameter.

- Subjects must have received at least one prior chemotherapy-containing regimen and at least one prior rituximab-containing regimen.

- Age > = 18 years.

- Accessible disease, defined as at least one of the following:

- Adenopathy accessible to core needle biopsy

- Bone marrow involvement

- Circulating lymphoma cells in the peripheral blood

- ECOG performance status < = 2

- Patients must have normal organ and marrow function as defined below within 14 days before enrollment:

- ANC > = 750 cells/uL

- platelets > = 75,000 cells/uL

- Hemoglobin > = 8.0 g/dL

- total bilirubin < = 1.5 times upper limit of normal

- AST(SGOT)/ALT(SGPT) < = 3 times upper limit of normal

- Calculated creatinine clearance > = 30 mL/min

- The effects of bortezomib and PD 0332991 on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, female subjects must either be post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) prior to study entry and for the duration of the study. Male subjects must agree to use adequate contraception prior to study entry and for the duration of study participation. Should a female subject become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

- Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.

- Subjects must be willing and able to comply with the scheduled visits, treatment plans, laboratory tests, and other procedures

Exclusion Criteria:

- Patients who have had chemotherapy, radiotherapy, antibodies, or investigational agents within 4 weeks prior to entering the study unless progression has been documented while on treatment, or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients may be receiving prednisone at a maximum dose of 10 mg/day orally, provided the dose has been stable during the prior two weeks before starting treatment.

- Patients may not be receiving any other investigational agents.

- Prior exposure to PD 0332991

- Prior exposure to bortezomib will only be permitted if there was a documented complete or partial response and progression occurred off therapy

- Patients must not have experienced significant hematologic (grade 4) or neuropathic toxicities (grade 3 or 4) due to prior bortezomib therapy

- Peripheral neuropathy > = grade 2 (CTCAEv3.0) within 14 days before enrollment.

- History of allergic reactions attributed to compounds of similar chemical or biologic composition to bortezomib (e.g. boron or mannitol).

- Contraindication to serial core needle biopsies

- Known HIV infection

- Known malabsorption syndrome that may affect absorption of the drug

- Known or suspected CNS involvement

- Uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

- Pregnant and lactating women are excluded from the study because the risks to an unborn fetus or potential risks in nursing infants are unknown. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.

- QTc > 470 msec

- Current use or anticipated need for food or drugs that are known potent CYP3A4 inhibitors, including their administration within 7-days prior to the first PD 0332991dose (i.e. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, posaconazole, erythromycin, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, nefazodone, diltiazem, atazanavir, amprenavir,and fosamprenavir)

- Current use or anticipated need for drugs that are known potent CYP3A4 inducers, including their administration within 14-days prior to the first PD 0332991 dose (i.e. carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, primidone, rifabutin, rifampin, and St. John's Wort).

- Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see Appendix 7), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
Weill Cornell Medical College
New York, New York, United States
Status: Recruiting
Contact: Peter Martin, MD -
Start Date
June 2010
Completion Date
November 2014
Weill Medical College of Cornell University
Weill Medical College of Cornell University
Record processing date processed this data on July 28, 2015 page