Palbociclib in Combination With Lenalidomide and Dexamethasone for Multiple Myeloma

This clinical trial is for men and women with multiple myeloma that has returned after
treatment (relapsed) or did not respond to prior treatment (refractory).

This is a phase 1 study of the addition of the PD 0332991 (Palbociclib) CDK4/CDK6 inhibitor
to lenalidomide / dexamethasone treatment in RRMM. The purpose of the study is to determine
the effectiveness of the combination of PD 0332991, lenalidomide and dexamethasone (PLD) in
treating relapsed/refractory multiple myeloma. PD 0332991 (Palbociclib) is an experimental
drug and is a pill taken by mouth. It works by blocking specific growth signals within cancer
cells. Lenalidomide (also called Revlimid) is approved for use with dexamethasone for people
with multiple myeloma who have received prior therapy. Study participants will receive
different doses of Palbociclib and lenalidomide depending on when they enroll in the study.
The study will help determine the maximum tolerated dose of the combination of the study
drugs. Treatment schedule (treatment cycles are 28 days):

- Palbociclib daily for Days 1-14 of each cycle

- Lenalidomide daily for Days 8-21 (or Days 1-21, depending on dose level) of each cycle

- Dexamethasone on Days 1, 8, 15 and 22 of each cycle. Participants will continue on study
treatment as long as they are responding to therapy and not experiencing unacceptable
side effects.

Inclusion Criteria:

- Subject must voluntarily sign and understand written informed consent.

- Subject is ≥18 years at the time of signing the consent form.

- Subject has histologically confirmed multiple myeloma that expresses phosphorylated
retinoblastoma protein (pRb), as assessed using a historical biopsy sample if
available, or a freshly obtained tumor sample.

- Subject has relapsed or refractory myeloma as defined by progression of disease either
after prior therapy or lack of response to currently used therapy.

- Subject must have received and relapsed or progressed after prior treatment with
bortezomib.

- Subject has measurable disease as defined by > 0.5 g/dL serum monoclonal protein, >10
mg/dL involved serum free light chain (either kappa or lambda) provided that the serum
free light chain ratio is abnormal, >0.2 g/24 hrs urinary M-protein excretion, and/or
measurable plasmacytoma(s) of at least 1cm in greatest dimension as measured by either
CT scanning or MRI.

- Subject has a Karnofsky performance status ≥60% (>50% if due to bony involvement of
myeloma

- Subject is able to take prophylactic anticoagulation as detailed in section 9.1
(patients intolerant to aspirin may use warfarin or low molecular weight heparin).

- Subject is registered into the mandatory Revlimid REMS®program, and is willing and
able to comply with the requirements of Revlimid REMS® program.

- If subject is a female of childbearing potential (FCBP), she must have a negative
serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14
days prior to and again within 24 hours of prescribing lenalidomide (prescriptions
must be filled within 7 days) and must either commit to continued abstinence from
heterosexual intercourse or begin TWO acceptable methods of birth control, one highly
effective method and one additional effective method AT THE SAME TIME, at least 28
days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy
testing. Men must agree to use a latex condom during sexual contact with females of
child bearing potential even if they have had a successful vasectomy. Men must agree
to continue birth control for 90 days post-last dose of PD-0332991

- All study participants must be registered into the mandatory Revlimid REMS® program,
and be willing and able to comply with the requirements of the REMS® program.

- Females of reproductive potential must adhere to the scheduled pregnancy testing as
required in the Revlimid REMS® program.

- Subject has a life expectancy ≥ 3 months

- Subjects must meet the following laboratory parameters:

- Absolute neutrophil count (ANC) ≥750 cells/mm3 (1.0 x 109/L)

- Platelet count ≥ 75,000/mm3 (75 x 109/L)

- Serum SGOT/AST <3.0 x upper limits of normal (ULN)

- Serum SGPT/ALT <3.0 x upper limits of normal (ULN)

- Serum creatinine clearance, (either calculated or directly measured). ≥ 60cc/min

- Serum total bilirubin <2.0 mg/dL (34 μmol/L)

Exclusion Criteria:

- Subject has immeasurable MM (no measurable monoclonal protein, free light chains in
blood or urine, or measureable plasmacytoma on radiologic scanning).

- Subject has a prior history of other malignancies unless disease free for ≥ 5 years,
except for basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the
cervix or breast, or localized prostate cancer with Gleason score < 7 with stable
prostate specific antigen (PSA) levels.

- Subject has had myocardial infarction within 6 months prior to enrollment , or
NYHA(New York Hospital Association) Class III or IV heart failure, Ejection Fraction <
35%, uncontrolled angina, severe uncontrolled ventricular arrhythmias,
electrocardiographic evidence of acute ischemia or active conduction system
abnormalities.

- Female subject who is pregnant or lactating.

- Subject has known HIV infection

- Subject has known active hepatitis B or hepatitis C infection.

- Subject has active viral or bacterial infections or any coexisting medical problem
that would significantly increase the risks of this treatment program.

- Subject has known hypersensitivity to dexamethasone or lenalidomide.

- Subject has a history of thromboembolic event within the past 4 weeks prior to
enrollment.

- Subject has any clinically significant medical or psychiatric disease or condition
that, in the Investigator's opinion, may interfere with protocol adherence or a
subject's ability to give informed consent.

- Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study.