Clinical trial NCT03904251: CPX-351 and Gemtuzumab Ozogamicin in Treating Patients With Relapsed Acute Myeloid Leukemia
Official title: A Phase Ib Trial With Dose Expansion Evaluating CPX-351 Plus Gemtuzumab Ozogamicin for Relapsed Acute Myelogenous Leukemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Acute Myelogenous Leukemia
Keywords: AML, Leukemia
Lead sponsor: Jonsson Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: Pfizer
name: Jazz Pharmaceuticals
name: University of California, Los Angeles
First posted: 2019-04-05
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase Ib trial studies the best dose of gemtuzumab ozogamicin when given together with CPX-351 in treating patients with acute myeloid leukemia that has come back after it was previously in remission. CPX-351 is a chemotherapy, which works in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Gemtuzumab ozogamicin is a monoclonal antibody, called gemtuzumab, linked to chemotherapy called calicheamicin. Gemtuzumab attaches to CD33 (transmembrane receptor) positive cancer cells in a targeted way and delivers ozogamicin to kill them. Giving CPX-351 and gemtuzumab ozogamicin may work better in treating patients with acute myeloid leukemia, compared to giving only one of these therapies alone.

Detailed description: PRIMARY OBJECTIVES:

I. To determine the phase II dose of the combination liposome-encapsulated daunorubicin-cytarabine (CPX-351) plus gemtuzumab ozogamicin (GO) by means of estimating maximum tolerated dose (MTD) in participants with relapsed acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

I. To estimate the remission rate (complete remission plus complete remission with incomplete hematologic recovery) of participants in the MTD cohort who receive CPX-351 plus GO.

II. To evaluate CPX-351 plus GO as a bridge to allogeneic hematopoietic stem cell transplantation (HSCT) in participants with relapsed AML.

III. To estimate the duration of remission. IV. To evaluate for toxicity by means of Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

V. To evaluate for the development of veno-occlusive disease at any point during the study in participants treated with CPX-351 plus GO.

VI. To evaluate time to return of normal hematopoiesis after induction therapy. VII. To evaluate 30- and 60-day survival.

EXPLORATORY OBJECTIVES:

I. To evaluate if there is a difference in remission rate based on CD33 splicing single nucleotide polymorphism (SNP) genotype (CC, TC, or TT) in participants receiving CPX-351 plus GO.

II. To evaluate the impact that leukemia cell multidrug resistance activity have on achieving remission after treatment with CPX-351 plus GO.

III. To evaluate the possible associations of participant constitutional genotype, leukemia genotype, and response to therapy.

IV. To evaluate the possible associations of participant ribonucleic acid (RNA) expression, leukemia RNA expression, and response to therapy.

OUTLINE: This is a dose-escalation study of gemtuzumab ozogamicin when given in combination with liposome-encapsulated daunorubicin-cytarabine.

INDUCTION: Patients receive liposome-encapsulated daunorubicin-cytarabine intravenously (IV) over 90 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 7 in the first cohort of study participants, days 4 and 7 in the second cohort of study participants, or days 1, 4, and 7 in the third cohort of study participants, in the absence of disease progression or unacceptable toxicity. The dose expansion cohort will receive the above treatment schedule that is determined to be the maximum tolerated dose.

CONSOLIDATION: Patients who achieve complete remission (CR)/CR with incomplete hematologic recovery (CRi) receive consolidation therapy at the discretion of the treating physician and/or proceed to allogeneic HSCT.

Eligibility criteria: Inclusion Criteria:

* Bone marrow blasts \>= 5% that develops after remission, no restriction on prior number of relapses or regimens
* Eastern Cooperative Oncology Group (ECOG) 0-2
* At least a 3-month duration of remission prior to relapse
* Participants with relapse after allogeneic transplantation are included
* Up to 1 cycle of hypomethylating agent monotherapy at time of relapse is allowed, must be discontinued at least 14 days prior to start of salvage induction
* Serum total bilirubin =\< 2.0 mg/dL, unless considered due to Gilbert?s disease or leukemia involvement
* Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =\< 3 times the upper limit of normal, unless considered due to leukemia involvement
* Alkaline phosphatase =\< 3 times the upper limit of normal, unless considered due to leukemia involvement
* Serum creatinine =\< 2.0 mg/dL, or creatinine clearance \> 40 mL/min based on Cockcroft-Gault glomerular filtration rate (GFR)
* Ability to give full informed consent on their own
* Females of reproductive potential (postmenopausal for less than 24 consecutive months) must have a negative pregnancy

Exclusion Criteria:

* Currently receiving targeted therapy for FLT3 (cytokine receptor tyrosine kinase class III), IDH1, or IDH2 (isocitrate dehydrogenase, 1, 2) mutations and intent to continue use; prior use of targeted therapy for such mutations is allowed, but agents should be discontinued 1 week prior to enrollment
* Acute promyelocytic leukemia
* Second malignancy that would limit survival by less than 2 years
* New York Heart Association class III or VI
* Left ventricular ejection fraction \< 50%
* History of coronary stent placement that requires mandatory continuation of dual-antiplatelet therapy
* History of Wilson?s disease or other copper handling disorders
* Hypersensitivity to cytarabine, daunorubicin, or liposomal products
* Active invasive fungal infection
* Active bacterial or viral infection manifesting as fevers or hemodynamic instability within the past 72 hours
* Lifetime cumulative daunorubicin-equivalent anthracycline dose \> 368 mg/m\^2

Primary outcomes:
measure: Maximum tolerated dose (MTD)
timeFrame: Up to day 42
Secondary outcomes:
measure: Objective response rate (ORR)
timeFrame: Up to day 42
measure: Proportion of participants who go on to receive allogeneic hematopoietic cell transplantation (HSCT) after achieving CR/CRi
timeFrame: Up to 18 months
measure: Duration of remission
timeFrame: Up to 18 months
measure: Incidence of toxicities
timeFrame: Up to day 42
measure: Diagnosis of veno-occlusive disease (VOD)
timeFrame: Up to 18 months
measure: Time to return of normal hematopoiesis
timeFrame: From day 1 of induction, assessed up to 18 months
measure: Number of participants deceased at day 30 and day 60
timeFrame: At 30 and 60 days following the start of induction
Other outcomes:
measure: Genotype at CD33 splicing single nucleotide polymorphism (SNP) RS12459419
timeFrame: Up to 18 months
measure: Multidrug resistance activity of leukemia cell P-glycoprotein (Pgp)
timeFrame: Up to 18 months
measure: Multidrug resistance activity of leukemia cell multidrug resistance protein 1 (MRD1)
timeFrame: Up to 18 months
measure: Exome sequencing analysis
timeFrame: Up to 18 months
measure: Ribonucleic acid (RNA) sequencing analysis
timeFrame: Up to 18 months
Locations:
city: Los Angeles
country: United States
facility: UCLA / Jonsson Comprehensive Cancer Center
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mount Zion
state: California
Study officials:
affiliation: UCLA / Jonsson Comprehensive Cancer Center
name: Caspian Oliai, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jentzsch M, Grimm J, Bill M, Brauer D, Backhaus D, Goldmann K, Schulz J, Niederwieser D, Platzbecker U, Schwind S. ELN risk stratification and outcomes in secondary and therapy-related AML patients consolidated with allogeneic stem cell transplantation. Bone Marrow Transplant. 2021 Apr;56(4):936-945. doi: 10.1038/s41409-020-01129-1. Epub 2020 Nov 19.