Clinical trial NCT02954653: A Study Of PF-06747143, As Single Agent Or In Combination With Standard Chemotherapy In Adult Patients With Acute Myeloid Leukemia
Official title: A PHASE 1 DOSE ESCALATION STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRAVENOUS PF-06747143, ADMINISTERED AS SINGLE AGENT OR IN COMBINATION WITH STANDARD CHEMOTHERAPY IN ADULT PATIENTS WITH ACUTE MYELOID LEUKEMIA
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Keywords: relapsed
refractory
acute myeloid leukemia
AML
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2016-11-03
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Primary purpose: TREATMENT

Brief summary: Two part, dose escalation and dose expansion study. Open label, multi center, non randomized, multiple dose, safety, pharmacokinetic and pharmacodynamic study of single agent PF-06747143 in sequential dose levels of adult patients with refractory or relapsed AML in order to establish maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D) or maximally permitted dose (MPD) following by a 3 arm dose expansion with PF-06747143 in combination with standard of care chemotherapy in adult patients with AML.

Detailed description: Patients will receive intravenous (IV) PF-06747143 as a weekly infusion (QW) in 28 day cycles at escalating doses. The proposed dosing scheme includes 0.3, 1.0, 3.0, 10, 15, and 20 mg/kg. Patients will be monitored for dose limiting toxicity (DLT) in the dose escalation in order to define the MTD. Two of the three arms in the dose expansion will include PF-06747143 in combination with standard of care chemotherapy and will include a safety lead in. The third arm, pending clinical data, will be PF-06747143 as a single agent.

Eligibility criteria: Inclusion Criteria:

Part 1 and Part 2 cohort 3: Patients diagnosed with AML ( bone marrow (BM) or peripheral blood (PB) blast counts \>/= 20%) and have received prior chemotherapy and/or standard of care and have relapsed, refractory or Minimal Residual Disease (defined as patients showing residual blast 10-14 days post-induction chemotherapy).

• Patients that are not candidates to receive standard of care and/or refusing the standard care of therapies will also be considered.

Part 2 - Cohort 1 and 2: Newly diagnosed, previously untreated de novo or secondary AML population (AML with bone marrow or peripheral blast counts 20%):

* Cohort 1: Fit to receive intensive remission induction chemotherapy.
* Cohort 2: Unfit to receive or not considered a candidate for intensive remission induction chemotherapy.

Part 1 and 2:

* Life expectancy at least 12 weeks.
* Hydroxyurea is allowed on study to control total peripheral white blood cell count but must be ceased 24 hours prior to first dose.
* Off of prior therapy for 2-4 weeks prior to first dose.
* ECOG performance status: 0 to 2.
* Resolved acute effects of any prior therapy.
* Adequate renal and hepatic function.

Exclusion Criteria:

* Patients with acute promyelocytic leukemia, AML with known central nervous system (CNS) involvement unless the patient has completed treatment for the CNS disease, has recovered from the acute effects of therapy prior to study entry, and is neurologically stable.
* Patient is known refractory to platelet or packed red cell transfusions per institutional guidelines.
* Prior treatment with a compound targeting CXCR4.
* Chronic systemic corticosteroid treatment.
* Known or suspected hypersensitivity to recombinant human proteins.
* Chronic graft versus host disease (GVHD), active GVHD with other than Grade 1 skin involvement, or GVHD requiring systemic immunosuppressive treatment (Part 1 and cohort 3).
* Not recovered from stem cell transplant associated toxicities (Part 1 and cohort 3).
* Prior treatment with hypomethylating agents or chemotherapy for antecedent myelodysplastic syndrome (MDS) (Part 2, cohort 2)
* AML associated with favorable risk karyotypes, including inv(16), t(8;21), t(16;16), or t(15;17) (cohort 2)
* Candidates for allogeneic stem cell transplant (Part 2, cohort 2)
* Known hypersensitivity to cytarabine or daunorubicin (Part 2, cohort 1) and decitabine or azacitidine or mannitol (Part 2, cohort 2).

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicities (DLTs) [Part 1]
timeFrame: Day 1 to Day 28 of Cycle 1
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) [Part 2]
timeFrame: 1 year
measure: Number of Participants With Laboratory Abnormalities [Part 2]
timeFrame: 1 year
measure: Objective Response Rate (ORR) - Percentage of Participants With Objective Response [Part 2]
timeFrame: 16 weeks
measure: Duration of Objective Response Rate (ORR) [Part 2]
timeFrame: 16 weeks
measure: Progression Free Survival [Part 2]
timeFrame: 16 weeks
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [Part 1]
timeFrame: 1 year
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) by Maximum National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Grade [Part 1]
timeFrame: 1 year
measure: Number of Participants With Hematology Laboratory Abnormalities by Type and Maximum National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Grade [Part 1]
timeFrame: 1 year
measure: Number of Participants With Chemistry Laboratory Abnormalities by Type and Maximum National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Grade [Part 1]
timeFrame: 1 year
measure: Objective Response Rate (ORR) - Percentage of Participants With Objective Response [Part 1]
timeFrame: 16 weeks
measure: Duration of Objective Response Rate (ORR) [Part 1]
timeFrame: 16 weeks
measure: Progression Free Survival [Part 1]
timeFrame: 16 weeks
measure: Incidence of Anti-Drug Antibodies (ADA) Against PF-06747143 [Part 1]
timeFrame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, end of treatment
measure: Incidence of Neutralizing Antibodies (Nab) Against PF-06747143 [Part 1]
timeFrame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, end of treatment
measure: Incidence of Anti-Drug Antibodies (ADA) and Neutralizing Antibodies (Nab) Against PF-06747143 [Part 2]
timeFrame: Days 1 and 15 pre-dose of Cycle 1, Day 1 pre-dose of Cycles 2-6, Day 1 pre-dose of every 3 cycles thereafter, and at end of treatment
measure: Maximum Observed Serum Concentration (Cmax) of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Time to Reach Maximum Observed Serum Concentration (Tmax) of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Area Under the Curve From Time Zero to Infinity (AUCinf) of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Apparent Volume of Distribution (Vd) of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Terminal Elimination Half-Life (t1/2) of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Clearance (CL) of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Maximum Serum Concentration at Steady State (Cmax,ss) of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Minimum Observed Serum Trough Concentration at Steady State (Cmin,ss) of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Area Under the Curve From Time Zero to End of Dosing Interval at Steady State (AUCtau,ss) of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Accumulation Ratio (Rac) of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Clearance (CL) at Steady State of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Volume of Distribution at Steady State (Vss) at of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Terminal Elimination Half-Life (t1/2) at Steady State of PF-06747143 [Parts 1 and 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
measure: Peak and Trough PF-06747143 Concentrations for Selected Doses [Part 2]
timeFrame: Cycle 1 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 1 Day 8 at 0 hour; Cycle 1 Day 15 at 0 and 1 hour; Cycle 1 Day 22 at 0 hour; Cycle 2 Day 1 at 0, 1, 24, 48, 96 hours; Cycle 2 Days 8, 15 and 22 at 0 hour; Subsequent cycles: Day 1 at 0 hour; End of treatment
Other outcomes:
Locations:
city: Tucson
country: United States
facility: The University of Arizona Cancer Center-North Campus
state: Arizona
city: Tucson
country: United States
facility: Banner-University Medical Center Tucson
state: Arizona
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Liu SH, Gu Y, Pascual B, Yan Z, Hallin M, Zhang C, Fan C, Wang W, Lam J, Spilker ME, Yafawi R, Blasi E, Simmons B, Huser N, Ho WH, Lindquist K, Tran TT, Kudaravalli J, Ma JT, Jimenez G, Barman I, Brown C, Chin SM, Costa MJ, Shelton D, Smeal T, Fantin VR, Pernasetti F. A novel CXCR4 antagonist IgG1 antibody (PF-06747143) for the treatment of hematologic malignancies. Blood Adv. 2017 Jun 21;1(15):1088-1100. doi: 10.1182/bloodadvances.2016003921. eCollection 2017 Jun 27.