Blinatumomab and Pembrolizumab for Adults With Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia With High Marrow Lymphoblasts

This is a Phase I/II study of blinatumomab in combination with pembrolizumab in adult
patients with relapsed or refractory B-lineage ALL The primary objective of this study is to
determine if the addition of pembrolizumab to blinatumomab improves the overall response rate
(CR+ CRh) relative to blinatumomab alone in adult subjects with relapsed or refractory B-cell
acute lymphoblastic leukemia with high bone marrow lymphoblast percentage.

Mechanisms of resistance to blinatumomab are not well understood although inhibition of or
suboptimal T-cell activation may play an important role. PD-L1 and PD-L2 expression and
upregulation in lymphoblasts and the bone marrow microenvironment at baseline and in response
to cytokines including those released upon blinatumomab exposure may inhibit T-cell function
through the PD-1 receptor and lead to resistance to blinatumomab. The investigators
hypothesize that part of the resistance to therapy with blinatumomab is mediated by the
exuberant cytokine release seen with higher disease burden leading to increased expression of
PD-L1 and PD-L2. Enhancing T-cell activity through use of the PD-1 inhibitor pembrolizumab is
predicted to augment the activity of blinatumomab and convert more patients to complete
remission and prolong remission durations. This study will also act to expand knowledge of
PD-L1 and PD-L2 dynamics in response to blinatumomab. It will also be a paradigm for the
addition of checkpoint inhibitors to therapy with bifunctional T-cell engaging antibodies
currently in development for targeting other liquid and solid tumors.

The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune
control. This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune
evasion and should be considered as an attractive target for therapeutic intervention.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands,
PD-L1 and PD-L2.

The study will be conducted in 2 stages:

Stage 1 is to ensure safety of pembrolizumab in combination with blinatumomab.

Stage 2 of the study will include an expansion cohort of up to 21 additional subjects (for a
total of 24 subjects) to evaluate the efficacy of the combination of blinatumomab and
pembrolizumab in adults with relapsed/refractory B-cell ALL

Inclusion Criteria:

- Relapsed or refractory B-lineage acute lymphoblastic leukemia having received at least
1 prior line of therapy

- Philadelphia chromosome/BCR-ABL1-positive B-lineage ALL must have failed at least 1
second or third generation tyrosine kinase inhibitor (TKI) or be intolerant to TKIs

- Greater than 50% lymphoblasts on screening bone marrow aspirate or biopsy

- Adequate organ function

- Women of child-bearing potential and men with partners of child-bearing potential must
agree to use 2 methods of birth control or be surgically sterile, or abstain from
heterosexual activity for the course of the study through 120 days after the last dose
of study medication.

- A woman of child-bearing potential is any female (regardless of sexual orientation,
having undergone a tubal ligation, or remaining celibate by choice) who meets the
following criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy; or

- Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months)

- Male subjects must agree to use a latex condom during sexual contact with females of
childbearing potential even if they have had a successful vasectomy starting with the
first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria:

- Allogeneic hematopoietic cell transplantation within 5 years of study drug
administration

- 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.

- GM-CSF or G-CSF use within 2 weeks of study treatment and throughout the study

- Prior checkpoint inhibitor therapy including anti-PD1, anti-PD-L1, anti-CTLA4, anti-
CD137, or anti-PD-L2 therapy

- Active CNS or testicular involvement by leukemia

- History of neurologic disorder

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy.

- Burkitt lymphoma/leukemia

- Has a diagnosis of congenital immunodeficiency

- Has a known history of active TB (Bacillus Tuberculosis)

- Known HIV infection

- Active hepatitis B or hepatitis C infection

- Has received a live vaccine within 30 days prior to first dose

- 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.

- History of autoimmune disease

- Known interstitial lung disease

- Any evidence of active, non-infectious pneumonitis or has a history of
(non-infectious) pneumonitis that required steroids or current pneumonitis

- Patients who have received chemotherapy or radiotherapy within 2 weeks prior to
entering the study or has not recovered from adverse events due to agents administered
more than 2 weeks earlier.

- Patients who are less than 4 weeks from surgery or have insufficient recovery from
surgical-related trauma or wound healing.

- Known impaired cardiac function