Escalating doses of PD 0332991 in combination with bortezomib will be studied sequentially,
with at least 3 patients in each dose level until the MTD is determined. PD 0332991 will be
given orally, starting on Day 1 of each cycle, once a day for 12 days followed by 9 days
without treatment. Bortezomib will be given by intravenous (IV) bolus or subcutaneously
(taking 3 to 5 seconds to administer) on days 8, 11, 15 and 18. For dose levels 3a and 4b,
bortezomib will be administered only on days 15 and 18. One cycle is defined as 3 weeks (21
days). Subjects will remain on treatment until they meet criteria for withdrawal from
treatment described in section 5.4 (e.g., DLT, disease progression, unacceptable toxicity, or
withdrawal of consent).
The pharmacist will maintain records of drug receipt (if applicable), drug preparation, and
dispensing, including the applicable lot numbers, patients' height, body weight, and body
surface area, and total drug administered in milliliters and milligrams. Any discrepancy
between the calculated dose and dose administered and the reason for the discrepancy must be
recorded in the source documents.
Treatment will be administered only to eligible patients under the supervision of the
investigator or identified sub-investigator (s). Treatment will be administered on an
outpatient basis. Reported adverse events and potential risks are described in Section 7.
Appropriate dose modifications are described in Section 6. No investigational or commercial
agents or therapies other than those described below may be administered with the intent to
treat the patient's malignancy.
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.
