The purpose of this study is to determine the most appropriate dose for the combination of
ibrutinib and pembrolizumab and to see if the combination is active for the disease. The
study will monitor for any side effects and if the combination of ibrutinib and pembrolizumab
works in the cancers being studied.
There will be 2 experimental drugs given to the subject in this study. One experimental drug
used in this study is called ibrutinib and the second is called pembrolizumab.
This is the first time that ibrutinib will be used in combination with pembrolizumab. This
combination is considered experimental. Experimental means that it is still being tested to
see if it is safe and effective. Ibrutinib is a new drug known as a 'Bruton's Tyrosine Kinase
(BTK) inhibitor'. Ibrutinib blocks an enzyme (protein) that affects how certain types of
blood cancer cells grow and survive. Blocking this enzyme is a very important mechanism in
killing blood cancer cells. Ibrutinib has been approved in the United States, Israel, and the
European Union for use in adult patients with mantle cell lymphoma (MCL) and adult patients
with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.
Pembrolizumab is an antibody (a type of human protein) that is being tested to see if it will
allow the body's immune system to work against tumor cells. Pembrolizumab is approved for use
by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with
melanoma (skin cancer) who have received prior treatments. Pembrolizumab is not FDA approved
to treat patients with chronic lymphocytic leukemia [CLL] and mantle cell lymphoma [MCL].
(1) Objective: a. (Phase 1) Assess the safety of fixed dose or, as needed, de-escalated
ibrutinib/pembrolizumab in patients with MCL (Cohort A) and CLL (Cohort B) to determine
recommended phase 2 dosing.
b. (Phase 2A): Assess CR rate of combination ibrutinib/pembrolizumab therapy, in comparison
to historical data of ibrutinib monotherapy, in patients with MCL (Cohort C) and CLL (Cohort
This is an open-label Phase 1/2A study, which consists of Phase 1 (Safety Assessment Cohorts)
utilizing a 3+3 dose de-escalation design and Phase 2A (Expansion Cohorts) utilizing a single
arm one-stage design.
All patients receive a 28 day lead-in of ibrutinib and thereafter, a treatment 'cycle' is
defined as a course of treatment of 21 days starting with the intravenous administration of
pembrolizumab on Day 1 of each cycle along with once daily oral intake of ibrutinib on all
1. The combination of ibrutinib and pembrolizumab will be safe and well tolerated.
2. The combination of ibrutinib and pembrolizumab will result in higher CR rates compared
to historic data of ibrutinib monotherapy in cohorts of CLL and MCL.
Secondary Objectives & Hypotheses
(1) Objective: (Phase 2A): Assess duration of response, overall response rate, and duration
of stable disease, compared to historical data of single agent ibrutinib, in patients with
MCL (Cohort C) and CLL (Cohort D).
Hypothesis: The combination of ibrutinib and pembrolizumab will increase duration of
response, overall response rate and duration of stable disease when compared to historical
data of single agent ibrutinib.
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be ³ 18 years of age on day of signing informed consent.c
3. Have measurable disease based on:
1. Lugano classification  (cohorts A,C)
2. International Workshop on CLL  (cohorts B,D)
4. Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days)
prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples
cannot be provided (e.g. inaccessible or subject safety concern) may submit an
archived specimen or leukemic blood sample, only upon written agreement from the Study
5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
6. Demonstrate adequate organ function as defined in Table 1, all screening labs should
be performed within 14 days of treatment initiation.
7. Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
8. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an
adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the
course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
9. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate
method of contraception as outlined in Section 5.7.1- Contraception, starting with the
first dose of study therapy through 120 days after the last dose of study therapy.
1. Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
3. Has a known history of active Bacillus Tuberculosis (TB)
4. Hypersensitivity to ibrutinib or pembrolizumab or any of their excipients.
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier.
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent.
- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.
- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
7. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.
8. Has known active central nervous system (CNS) metastases and/or lymphomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not include
lymphomatous meningitis which is excluded regardless of clinical stability.
9. Has active autoimmune disease that has required systemic treatment in the past 1 year
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
10. Has known history of, or any evidence of active, non-infectious pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating Investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
16. Has previously received a btk inhibitor and had progressive disease during therapy.
Patients who have previously discontinued btk inhibitor therapy because of intolerance
may be considered for eligibility per the assessment of the PI and treating physician
if there is reason that the patient may better tolerate btk inhibitor therapy at
enrollment versus previously.
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., hepatitis C
virus (HCV) RNA [qualitative] is detected).
19. Has received a live vaccine within 30 days of planned start of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.