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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
8
PF 06747143 is a humanized IgG1 monoclonal antibody (mAb) that is an antagonist of CXCR4.
100-200 mg/m2 continuous infusion for 7 days)
60-90 mg/m2 daily for 3 days
The University of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
Banner-University Medical Center Tucson
Tucson, Arizona, United States
The University of Chicago Medical Center
Chicago, Illinois, United States
Wake Forest Baptist Health
Winston-Salem, North Carolina, United States
Number of Participants With Dose-Limiting Toxicities (DLTs) [Part 1]
DLTs were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 and were defined as any of a predefined set of unacceptable hematologic and non-hematologic adverse events (AEs) occurring in the first treatment cycle unless clearly determined unrelated to PF-06747143. In addition, clinically important or persistent toxicities that were not included in the pre-specified criteria could be considered a DLT following review by the investigators and sponsor.
Time frame: Day 1 to Day 28 of Cycle 1
Number of Participants With Treatment-Emergent Adverse Events (AEs) [Part 2]
An AE was any untoward medical occurrence in a participant administered a product or medical device without regard to possibility of causal relationship. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment.
Time frame: 1 year
Number of Participants With Laboratory Abnormalities [Part 2]
Following parameters were to be analyzed for laboratory examination: hematology (hemoglobin, platelets, white blood cell \[WBC\], absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils, absolute basophils, percent blast cells); chemistry (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], alkaline phosphatase, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, blood urea nitrogen or urea, creatinine, uric acid, glucose \[non-fasted\], albumin, phosphorous or phosphate); coagulation (prothrombin time \[PT\] or international normalized ratio \[INR\], partial thromboplastin time \[PTT\] or activated PTT \[aPTT\]); urinalysis (urine dipstick for urine protein: if positive collect 24 hours and microscopic \[reflex testing\]; urine dipstick for urine blood: if positive collect a microscopic \[reflex testing\]); pregnancy test (for female participants of childbearing potential, serum or urine).
Time frame: 1 year
Objective Response Rate (ORR) - Percentage of Participants With Objective Response [Part 2]
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75 mg/m2 sub-cutaneous or intravenous for 7 days)
20 mg/m2 continuous intravenous infusion for 5 days in a 4-week schedule
Objective Response was defined as morphologic leukemia-free state (MLFS), complete remission (CR), cytogenetic CR (CRc), molecular CR (CRm), partial remission (PR), or CR or PR with incomplete blood count recovery (CRi or PRi). MLFS: Bone marrow (BM) blasts \<5%; absence of blasts with Auer rods and extramedullary disease (EMD). CR: MLFS criteria; absolute neutrophil count (ANC)\>1000/ul and platelet \>100,000/ul; independence from red cell transfusions. CRc: Reversion to a normal karyotype at the time of CR in cases with an abnormal karyotype at the time of diagnosis; based on the evaluation of 20 metaphase cells from BM. CRm: Reversion to a molecular-negative phenotype at the time of CR. CRi: All CR criteria except for ANC \<1000/ul or platelet \<100,000/ul. PR: ANC \>1000/ul and platelet \>100,000/ul; BM blasts decreased to 5-25% and ≥50% decrease from pre-treatment levels. PRi: ANC \<1000/ul or platelet \<100,000/ul; BM blasts decreased to 5-25% and ≥50% decrease from pre-treatment levels.
Time frame: 16 weeks
Duration of Objective Response Rate (ORR) [Part 2]
Duration of ORR is the time from first documentation of MLFS, CR, CRc, CRm, PR, CRi or PRi to date of first documentation of disease progression or death due to any cause. MLFS: BM blasts \<5%; absence of blasts with Auer rods and EMD. CR: MLFS criteria; ANC\>1000/ul and platelet \>100,000/ul; independence from red cell transfusions. CRc: Reversion to a normal karyotype at the time of CR in cases with an abnormal karyotype at the time of diagnosis; based on the evaluation of 20 metaphase cells from BM. CRm: Reversion to a molecular-negative phenotype at the time of CR. CRi: All CR criteria except for ANC \<1000/ul or platelet \<100,000/ul. PR: ANC \>1000/ul and platelet \>100,000/ul; BM blasts decreased to 5-25% and ≥50% decrease from pre-treatment levels. PRi: ANC \<1000/ul or platelet \<100,000/ul; BM blasts decreased to 5-25% and ≥50% decrease from pre-treatment levels. Disease progression/relapse: BM blast ≥5%; or reappearance of blast in the blood; or development of EMD.
Time frame: 16 weeks
Progression Free Survival [Part 2]
Progression/relapse free survival is the time from the start of study treatment to first documentation of disease progression or to death due to any cause, whichever occurrs first. Disease progression/relapse: Bone marrow blast ≥ 5%; or reappearance of blast in the blood; or development of extramedullary disease (EMD).
Time frame: 16 weeks
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [Part 1]
An AE was any untoward medical occurrence in a participant administered a product or medical device without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening experience (immediate risk of dying); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. AEs included non-serious AEs and SAEs. Causality to study treatment was determined by the investigator.
Time frame: 1 year
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]
An AE was any untoward medical occurrence in a participant administered a product or medical device without regard to possibility of causal relationship. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. AEs were graded by the investigator according to NCI CTCAE version 4.03 (Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE). AEs included non-serious AEs and SAEs.
Time frame: 1 year
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]
Hematology laboratory abnormalities included anemia, hemoglobin increased, lymphocyte count increased, lymphopenia, neutrophil count decreased, platelet count decreased, and white blood cell (WBC) decreased. Each laboratory parameter was graded per NCI CTCAE version 4.03.
Time frame: 1 year
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]
Chemistry laboratory abnormalities included alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), bilirubin (total), creatinine, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, and hypophosphatemia. Each laboratory parameter was graded per NCI CTCAE version 4.03.
Time frame: 1 year
Objective Response Rate (ORR) - Percentage of Participants With Objective Response [Part 1]
Objective Response was defined as morphologic leukemia-free state (MLFS), complete remission (CR), cytogenetic CR (CRc), molecular CR (CRm), partial remission (PR), or CR or PR with incomplete blood count recovery (CRi or PRi). MLFS: Bone marrow (BM) blasts \<5%; absence of blasts with Auer rods and extramedullary disease (EMD). CR: MLFS criteria; absolute neutrophil count (ANC)\>1000/ul and platelet \>100,000/ul; independence from red cell transfusions. CRc: Reversion to a normal karyotype at the time of CR in cases with an abnormal karyotype at the time of diagnosis; based on the evaluation of 20 metaphase cells from BM. CRm: Reversion to a molecular-negative phenotype at the time of CR. CRi: All CR criteria except for ANC \<1000/ul or platelet \<100,000/ul. PR: ANC \>1000/ul and platelet \>100,000/ul; BM blasts decreased to 5-25% and ≥50% decrease from pre-treatment levels. PRi: ANC \<1000/ul or platelet \<100,000/ul; BM blasts decreased to 5-25% and ≥50% decrease from pre-treatment levels.
Time frame: 16 weeks
Duration of Objective Response Rate (ORR) [Part 1]
Duration of ORR is the time from first documentation of MLFS, CR, CRc, CRm, PR, CRi or PRi to date of first documentation of disease progression or death due to any cause. MLFS: BM blasts \<5%; absence of blasts with Auer rods and EMD. CR: MLFS criteria; ANC\>1000/ul and platelet \>100,000/ul; independence from red cell transfusions. CRc: Reversion to a normal karyotype at the time of CR in cases with an abnormal karyotype at the time of diagnosis; based on the evaluation of 20 metaphase cells from BM. CRm: Reversion to a molecular-negative phenotype at the time of CR. CRi: All CR criteria except for ANC \<1000/ul or platelet \<100,000/ul. PR: ANC \>1000/ul and platelet \>100,000/ul; BM blasts decreased to 5-25% and ≥50% decrease from pre-treatment levels. PRi: ANC \<1000/ul or platelet \<100,000/ul; BM blasts decreased to 5-25% and ≥50% decrease from pre-treatment levels. Disease progression/relapse: BM blast ≥5%; or reappearance of blast in the blood; or development of EMD.
Time frame: 16 weeks
Progression Free Survival [Part 1]
Progression/relapse free survival is the time from the start of study treatment to first documentation of disease progression or to death due to any cause, whichever occurrs first. Disease progression/relapse: Bone marrow blast ≥ 5%; or reappearance of blast in the blood; or development of extramedullary disease (EMD).
Time frame: 16 weeks
Incidence of Anti-Drug Antibodies (ADA) Against PF-06747143 [Part 1]
Samples were tested for ADA using a validated assay. Number of participants with positive ADA samples was determined.
Time frame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, end of treatment
Incidence of Neutralizing Antibodies (Nab) Against PF-06747143 [Part 1]
Samples tested positive for ADA were to be further analyzed for Nab using a validated assay.
Time frame: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, end of treatment
Incidence of Anti-Drug Antibodies (ADA) and Neutralizing Antibodies (Nab) Against PF-06747143 [Part 2]
Samples were to be analyzed for ADA using a validated assay. ADA positive samples were to be further analyzed for Nab using a validated assay.
Time frame: 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
Maximum Observed Serum Concentration (Cmax) of PF-06747143 [Parts 1 and 2]
Cmax of PF-06747143 was the peak serum concentration to be observed directly from data.
Time frame: 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
Time to Reach Maximum Observed Serum Concentration (Tmax) of PF-06747143 [Parts 1 and 2]
Tmax of PF-06747143 was to be observed directly from data as time of first occurrence of peak serum concentration.
Time frame: 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
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-06747143 [Parts 1 and 2]
AUClast is area under the serum concentration versus time profile from time zero to the time of the last quantifiable concentration.
Time frame: 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
Area Under the Curve From Time Zero to Infinity (AUCinf) of PF-06747143 [Parts 1 and 2]
AUCinf is area under the serum concentration versus time profile from time zero extrapolated to infinite time. If data permitted, AUCinf was to be estimated.
Time frame: 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
Apparent Volume of Distribution (Vd) of PF-06747143 [Parts 1 and 2]
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.
Time frame: 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
Terminal Elimination Half-Life (t1/2) of PF-06747143 [Parts 1 and 2]
t1/2 is the time measured for the serum concentration to decrease by one half. If data permitted, t1/2 was to be estimated.
Time frame: 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
Clearance (CL) of PF-06747143 [Parts 1 and 2]
CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Time frame: 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
Maximum Serum Concentration at Steady State (Cmax,ss) of PF-06747143 [Parts 1 and 2]
Assuming steady state was achieved, Cmax,ss was to be determined following multiple dosing to characterize the PK.
Time frame: 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
Minimum Observed Serum Trough Concentration at Steady State (Cmin,ss) of PF-06747143 [Parts 1 and 2]
Cmin is the minimum observed serum concentration. Assuming steady state was achieved, Cmin,ss was to be determined following multiple dosing to characterize the PK.
Time frame: 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
Area Under the Curve From Time Zero to End of Dosing Interval at Steady State (AUCtau,ss) of PF-06747143 [Parts 1 and 2]
AUCtau is area under the serum concentration versus time profile from time zero to the time tau (ie, dosing interval). Assuming steady state was achieved, AUCtau,ss was to be determined following multiple dosing to characterize the PK.
Time frame: 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
Accumulation Ratio (Rac) of PF-06747143 [Parts 1 and 2]
Accumulation ratio (Rac) was to be obtained from AUCtau at steady state (AUCtau,ss) divided by AUCtau after single dose.
Time frame: 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
Clearance (CL) at Steady State of PF-06747143 [Parts 1 and 2]
If data permitted, CL was to be determined following multiple dosing to characterize the PK.
Time frame: 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
Volume of Distribution at Steady State (Vss) at of PF-06747143 [Parts 1 and 2]
Vss is the apparent volume of distribution at steady-state. If data permitted, Vss was to be determined following multiple dosing to characterize the PK.
Time frame: 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
Terminal Elimination Half-Life (t1/2) at Steady State of PF-06747143 [Parts 1 and 2]
t1/2 is the time measured for the serum concentration to decrease by one half.
Time frame: 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
Peak and Trough PF-06747143 Concentrations for Selected Doses [Part 2]
Peak and trough PF-06747143 concentrations were to be observed directly from data.
Time frame: 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