The proposed study is a single-arm, multi-center, open-label phase II study of the
combination of palbociclib and ibrutinib in patients with previously treated mantle cell
lymphoma to evaluate the efficacy of this combination, with the primary objective of the
study being to assess median PFS and the secondary objectives to include ORR, CR, DOR, OS and
toxicity. Subjects will be enrolled and treated with palbociclib and ibrutinib with each
cycle of therapy being 28 days. Treatment will be based on the recommended phase II dose
(RP2D) from the phase I combination trial.
Treatment will consist of:
- Palbociclib administered at 100 mg oral once daily for 21 days on followed by 7 days off
- Ibrutinib administered at 560 mg oral continuously
Patients will continue to receive study drugs until disease progression, unacceptable
toxicity, or withdrawal of consent. If at any time one of the agents is held due to toxicity,
the other agent may be continued in those patients who are receiving clinical benefit.
Response will be assessed by PET/CT and/or CT every 3 cycles while on therapy for the first
year and then every 6 cycles thereafter until disease progression or at the investigator's
discretion if otherwise medically indicated. A PET will be required to confirm CR. A bone
marrow biopsy will be performed in patients with bone marrow involvement at the start of
therapy to confirm complete response once patients have otherwise met criteria for CR.
Inclusion Criteria:
1. Subjects must have histologically or cytologically confirmed MCL as defined by the
World Health Organization. All patients must have either t(11;14) by karyotype or
fluorescent in-situ hybridization (FISH) or positive immunohistochemistry (IHC) for
cyclin D1.
2. Subjects must have measurable disease defined as at least one tumor lesion of at least
1.5 cm by CT or MRI, PET positive lesion(s) or a peripheral blood CD5+, CD19+
lymphocyte count of at least 5,000 cells/µL.
3. Subjects must have received at least one prior systemic therapy.
4. Subjects who have received prior autologous stem cell transplant are eligible.
Patients that have undergone prior allogeneic stem cell transplant will only be
eligible if the patient is no longer taking immunosuppressive therapy and there are no
significant ongoing transplant-related adverse effects.
5. Subjects must be age ≥ 18 years
6. ECOG performance status ≤ 2
7. Subjects that have received either prior BTK inhibitor or CDK4/6 inhibitor will not be
eligible
8. Patients must have normal organ and marrow function as defined below:
9. Laboratory Values:
- ANC ≥ 1000 cells/μL;
- Platelets ≥ 75,000 cells/μL;
- Calculated creatinine clearance ≥30mL/min;
- AST or ALT ≤ 2.5x ULN;
- Total bilirubin ≤ 1.5x ULN;
- QTc ≤ 480 ms
10. Subjects must be able to provide written, informed consent
11. Subjects must have recovered from adverse events to ≤ grade 1 from prior therapies
12. Subjects must be able and willing to swallow and retain oral medication without a
condition that would interfere with enteric absorption
13. Subjects may be receiving prednisone at a maximum dose of 20 mg orally daily for
symptom control.
14. Serum or urine pregnancy test must be negative within 7 days of starting study
treatment in women of childbearing potential. Women of childbearing potential and men
with female partners who are able to become pregnant are required to use a highly
effective form of barrier contraception for the duration of the study and for 90 days
after the last dose of study drug. Adequate contraception is defined as abstinence or
two forms non hormonal contraception, which is a combination of two forms of the
following:
- Condom with spermicidal foam/gel/cream/suppository
- occlusive cap (diaphragm or cervical vault caps) with spermicidal
- non hormonal intrauterine device (IVD)
15. No evidence of active hepatitis B or C infections (i.e., no positive serology for
anti-HBc or anti-HCV antibodies)
16. HBV seropositive patients (HBsAg +) are eligible if they are closely monitored for
evidence of active HBV infection by HBV DNA testing and receive suppressive therapy
with lamivudine or other HBV suppressive therapy until 6 months after the last
rituximab dose.
17. Patients with HIV infection are eligible, provided they meet the following:
- No evidence of coinfection with hepatitis B or C
- CD4+ cell count ≥ 400/mm3
- No evidence of resistant strains of HIV
- If not on anti-HIV therapy, HIV viral load < 10,000 copies HIV RNA/mL If on
anti-HIV therapy, HIV viral load < 50 copies HIV RNA/mL
- No history of AIDS-defining conditions
- No use of strong CYP3A4/5 inhibitors or inducers
Exclusion Criteria:
1. Subjects with known or suspected CNS involvement
2. Concurrent therapy with other investigational products
3. History of allergic reactions attributed to compounds of chemical or biologic
composition similar to palbociclib
4. Subjects receiving any medications or substances that are strong or moderate
inhibitors or strong inducers of CYP3A isoenzymes within 7 days of starting study
treatment (See Appendix II)
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, diabetes, or psychiatric illness/social situations that would limit
compliance with study requirements.
6. Subjects with myocardial infarction within 6 months prior to enrollment or has New
York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina,
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities are not eligible. Prior to study
entry, any ECG abnormality at screening has to be documented by the investigator as
not medically relevant.
7. Pregnant women, or women of childbearing potential without a negative pregnancy test
(serum or urine) within 7 days prior to registration, irrespective of the method of
contraception used, are excluded from this study because the effect of palbociclib on
a developing fetus is unknown. Breastfeeding should be discontinued prior to study
entry.
8. Subjects must agree to use barrier contraceptive methods throughout the study period
up until at least 90 days post last palbociclib dose.
9. Subjects with clinically significant history of liver disease, including viral or
other known hepatitis, current alcohol abuse, or cirrhosis, etc.
10. Subjects with another active malignancy that limits survival
11. Subjects with a bleeding diathesis are not eligible.
12. Subjects with transfusion-dependent thrombocytopenia are not eligible.
