Back to resultsA Study Of PF-06747143, As Single Agent Or In Combination With Standard Chemotherapy In Adult Patients With Acute Myeloid Leukemia
Primary Purpose
Acute Myeloid Leukemia
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
PF-06747143
Cytarabine
Daunorubicin
Azacitidine
Decitabine
Sponsored by
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring relapsed, refractory, acute myeloid leukemia, AML
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).
Sites / Locations
- The University of Arizona Cancer Center-North Campus
- Banner-University Medical Center Tucson
- The University of Chicago Medical Center
- Wake Forest Baptist Health
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Active Comparator
Active Comparator
Experimental
Arm Label
Dose Escalation
Cohort 1
Cohort 2
Cohort 3
Arm Description
Single agent PF-06747143 dose escalation
PF-06747143 with standard dose cytarabine and daunorubicin.
PF-06747143 in combination with Azacitidine or Decitabine.
PF-06747143 dose expansion as a single agent.
Outcomes
Primary Outcome Measures
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.
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.
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).
Objective Response Rate (ORR) - Percentage of Participants With Objective Response [Part 2]
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.
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.
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).
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Peak and Trough PF-06747143 Concentrations for Selected Doses [Part 2]
Peak and trough PF-06747143 concentrations were to be observed directly from data.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02954653
Brief Title
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
2. Study Status
Record Verification Date
November 2019
Overall Recruitment Status
Terminated
Why Stopped
The study was terminated due to a change in sponsor prioritization.
Study Start Date
November 28, 2016 (Actual)
Primary Completion Date
December 5, 2017 (Actual)
Study Completion Date
December 5, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Pfizer
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia
Keywords
relapsed, refractory, acute myeloid leukemia, AML
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
8 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Dose Escalation
Arm Type
Experimental
Arm Description
Single agent PF-06747143 dose escalation
Arm Title
Cohort 1
Arm Type
Active Comparator
Arm Description
PF-06747143 with standard dose cytarabine and daunorubicin.
Arm Title
Cohort 2
Arm Type
Active Comparator
Arm Description
PF-06747143 in combination with Azacitidine or Decitabine.
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
PF-06747143 dose expansion as a single agent.
Intervention Type
Biological
Intervention Name(s)
PF-06747143
Intervention Description
PF 06747143 is a humanized IgG1 monoclonal antibody (mAb) that is an antagonist of CXCR4.
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Intervention Description
100-200 mg/m2 continuous infusion for 7 days)
Intervention Type
Drug
Intervention Name(s)
Daunorubicin
Intervention Description
60-90 mg/m2 daily for 3 days
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Intervention Description
75 mg/m2 sub-cutaneous or intravenous for 7 days)
Intervention Type
Drug
Intervention Name(s)
Decitabine
Intervention Description
20 mg/m2 continuous intravenous infusion for 5 days in a 4-week schedule
Primary Outcome Measure Information:
Title
Number of Participants With Dose-Limiting Toxicities (DLTs) [Part 1]
Description
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
Title
Number of Participants With Treatment-Emergent Adverse Events (AEs) [Part 2]
Description
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
Title
Number of Participants With Laboratory Abnormalities [Part 2]
Description
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
Title
Objective Response Rate (ORR) - Percentage of Participants With Objective Response [Part 2]
Description
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
Title
Duration of Objective Response Rate (ORR) [Part 2]
Description
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
Title
Progression Free Survival [Part 2]
Description
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
Secondary Outcome Measure Information:
Title
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [Part 1]
Description
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
Title
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]
Description
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
Title
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]
Description
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
Title
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]
Description
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
Title
Objective Response Rate (ORR) - Percentage of Participants With Objective Response [Part 1]
Description
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
Title
Duration of Objective Response Rate (ORR) [Part 1]
Description
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
Title
Progression Free Survival [Part 1]
Description
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
Title
Incidence of Anti-Drug Antibodies (ADA) Against PF-06747143 [Part 1]
Description
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
Title
Incidence of Neutralizing Antibodies (Nab) Against PF-06747143 [Part 1]
Description
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
Title
Incidence of Anti-Drug Antibodies (ADA) and Neutralizing Antibodies (Nab) Against PF-06747143 [Part 2]
Description
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
Title
Maximum Observed Serum Concentration (Cmax) of PF-06747143 [Parts 1 and 2]
Description
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
Title
Time to Reach Maximum Observed Serum Concentration (Tmax) of PF-06747143 [Parts 1 and 2]
Description
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
Title
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-06747143 [Parts 1 and 2]
Description
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
Title
Area Under the Curve From Time Zero to Infinity (AUCinf) of PF-06747143 [Parts 1 and 2]
Description
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
Title
Apparent Volume of Distribution (Vd) of PF-06747143 [Parts 1 and 2]
Description
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
Title
Terminal Elimination Half-Life (t1/2) of PF-06747143 [Parts 1 and 2]
Description
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
Title
Clearance (CL) of PF-06747143 [Parts 1 and 2]
Description
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
Title
Maximum Serum Concentration at Steady State (Cmax,ss) of PF-06747143 [Parts 1 and 2]
Description
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
Title
Minimum Observed Serum Trough Concentration at Steady State (Cmin,ss) of PF-06747143 [Parts 1 and 2]
Description
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
Title
Area Under the Curve From Time Zero to End of Dosing Interval at Steady State (AUCtau,ss) of PF-06747143 [Parts 1 and 2]
Description
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
Title
Accumulation Ratio (Rac) of PF-06747143 [Parts 1 and 2]
Description
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
Title
Clearance (CL) at Steady State of PF-06747143 [Parts 1 and 2]
Description
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
Title
Volume of Distribution at Steady State (Vss) at of PF-06747143 [Parts 1 and 2]
Description
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
Title
Terminal Elimination Half-Life (t1/2) at Steady State of PF-06747143 [Parts 1 and 2]
Description
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
Title
Peak and Trough PF-06747143 Concentrations for Selected Doses [Part 2]
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pfizer CT.gov Call Center
Organizational Affiliation
Pfizer
Official's Role
Study Director
Facility Information:
Facility Name
The University of Arizona Cancer Center-North Campus
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85719
Country
United States
Facility Name
Banner-University Medical Center Tucson
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724
Country
United States
Facility Name
The University of Chicago Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Wake Forest Baptist Health
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
Citations:
PubMed Identifier
29296751
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.
Results Reference
derived
Links:
URL
https://pmiform.com/clinical-trial-info-request?StudyID=B7861002
Description
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Learn more about this trial
A Study Of PF-06747143, As Single Agent Or In Combination With Standard Chemotherapy In Adult Patients With Acute Myeloid Leukemia
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