A Phase 1B Dose Escalation Study to Investigate the Safety, Tolerability and Preliminary Efficacy for the Combination of Dasatinib (BMS-354825) plus Nivolumab (BMS-936558) in Patients with Chronic Myeloid Leukemia (CML)

Summary

This is a phase 1B trial with an escalation and expansion cohort investigating the combination of dasatinib and nivolumab in subjects with CML-CP and CML-aP, who are progressing on, resistant to, suboptimally responding to, or intolerant of prior treatment with any Tyrone Kinase inhibitors (TKi) (except dasatinib in case of prior intolerance).

Study Population:
approx. treated 45 - 69

Treatments
x Dose level -1: De-escalation dose: nivolumab 0.3 mg/kg q 2 weeks + dasatinib 100 mg QD (CP) or 140 mg QD (aP)
x Dose level 1: nivolumab 1 mg/kg q 2 weeks + dasatinib 100 mg QD (CP) or 140 mg QD (aP)
x Dose level 2: nivolumab 3 mg/kg q 2 weeks + dasatinib 100 mg QD (CP) or 140 mg QD (aP)

Dose expansion Phase (21 - 33 subjects)
Subjects progressing resistant to, suboptimally responding to or intolerant to prior TKis (except dasatinib in case of
prior intolerance)

Dasatinib will be administered at standard doses appropriate for the phase of CML. The dasatinib (starting) dose will be as per the current dasatinib prescribing information for these subject populations: 100 mg daily for CML-CP and 140 mg for CML-aP. These doses were chosen in studies defining the optimal dose and schedule for monotherapy dasatinib and summarized in the Section 1.4.2 and in the current version of the dasatinib investigators Brochure. Due to large inter-subject variability in dasatinib PK, it is not believed that the different dasatinib doses for CML-CP and CML-aP subjects will lead to dramatically different tolerability when combined with nivolumab. Therefore, subjects on both doses will be included in each dosing cohort

The starting dose for this trial of 1 mg/kg every 2 weeks is tolerable as a single agent and is within the range that has shown anti-tumor activity in solid tumors. The maximum nivolumab dose in this trial of 3 mg/kg every 2 weeks is the same dose and schedule used in global Phase 3 studies. a dose de-escalation of nivolumab to 0.3 mg/kg maybe investigated, depending on the safety profile at 1 mg/kg.

Study enpoints:
The primary is to assess the safety and tolerability for the combination of dasatinib and
nivolumab in subjects with chronic phase or accelerated phase CML, in order to select a Phase 2
dose. The assessment of safety and tolerability will be based on:
* Dose limiting toxicities
* incidences of adverse events
* incidences of serious adverse events
* Frequencies of clinical laboratory tests by worst toxicity grade.

Participant Eligibility

1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/EC approved written informed consent form
in accordance with regulatory and institutional guidelines. This must be obtained before
the performance of any protocol related procedures that are not part of normal subject
care
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule,
laboratory testing, and other requirements of the study
2. Target Population
a) Confirmed diagnosis of CML, in chronic phase (CP) or AP:
i) With historically documented either cytogenetic Ph+ cells on Bone Marrow Aspirates
(BMA) or molecular results from peripheral blood
ii) >= 2 prior TKI therapies for CML
iii) Meeting one of the following criteria:
(1) Progression, resistance or suboptimal response to most recent prior Abl-kinase
inhibitor (imatinib, nilotinib ponatinib, bosutinib or dasatinib)-(see Appendix 4)
(2) Intolerance to most recent prior TKI (other than dasatinib) at the lowest possible
effective dose.
A subject is defined as being intolerant to prior TKI (other than dasatinib) if he or she had
a Grade >= 3 toxicity considered at least possibly related to that TKI at standard doses
which led to discontinuation of therapy. Subjects intolerant to prior dasatinib
(experiencing a grade >= 2 adverse event requiring discontinuation) are excluded.
b) Subject Re-enrollment: This study permits the re-enrollment of a subject that has
discontinued the study as a pre-treatment failure (ie, subject has not been treated) after
obtaining agreement from the Medical Monitor prior to re-enrolling a subject. If reenrolled,
the subject must be re-consented.
c) ECOG Performance Status (PS) Score 0 - 1
d) Toxicity of any prior therapy must have returned to Grade 0 - 1 (Grade 2 for hematologic) or be considered irreversible.
3. Age and Reproductive Status
a) Men and women, ages 18 years and older
b) Women of childbearing potential (WOCBP) who are sexually active or plan to become
sexually active must use two methods of contraception starting at the time of enrollment
to the study and for the entire treatment period until 23 weeks after the last dose of
nivolumab and 1 month after the last dose of dasatinib to minimize the risk of
pregnancy. At least one of the two methods selected must be regarded as a highly
effective method of contraception.
c) Women must have a negative serum or urine pregnancy test (minimum sensitivity
25 IU/L or equivalent units of human chorionic gonadotrophin (HCG) within 24 hours
prior to the start of the investigational product
d) Women must not be breastfeeding
e) Sexually active fertile men must use highly effective birth control if their partners are
WOCBP. Men that are sexually active with WOCBP must follow instructions for birth
control for the entire duration of 1 week before the study and up to 31 weeks after the last
dose of Nivolumab and up to 90 days after the last dose of dasatinib
f) Women who are not of childbearing potential (ie, who are postmenopausal or surgically
sterile azoospermic men do not require contraception.