Clinical trial NCT04038437: A Trial of CPX-351 Lower Intensity Therapy (LIT) Plus Venetoclax as First Line Treatment for Subjects With AML
Official title: A Phase 1b Trial of CPX-351 Lower Intensity Therapy (LIT) Plus Venetoclax as First Line Treatment for Subjects With AML Who Are Unfit for Intensive Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Keywords: CPX-351
Vyxeos
Venetoclax
Unfit
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2019-07-30
Enrollment: 35
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: Study CPX351-103 is an open-label, multicenter, phase 1b, safety and PK study to determine the MTD of the combination of CPX 351 and venetoclax when administered to subjects with newly diagnosed AML who are unfit for intensive chemotherapy (ICT) and to determine the recommended phase 2 dose (RP2D) for the Expansion Phase. This study will comprise 2 phases: a Dose Exploration Phase (Part 1) and an Expansion Phase (Part 2), in which all subjects will receive a combination of CPX-351 and venetoclax.


Eligibility criteria: Inclusion Criteria:

• Subject must have newly diagnosed AML with histological confirmation by World Health Organization (WHO) criteria.

Definition of subjects who are unfit for ICT:

• Each subject must meet the following criteria characterizing him / her as unfit to receive ICT prior to the first day of therapy to be enrolled in the study:

* ≥ 75 years of age OR
* ≥ 18 to 74 years of age and fulfilling at least 1 criteria associated with lack of fitness for ICT as follows:

  * Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 to 3;
  * Cardiac history of Congestive Heart Failure (CHF) requiring treatment or left ventricular ejection fraction (LVEF) ≤ 50%.
  * Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) ≤ 65% or Forced Expiratory Volume in 1 second (FEV1) ≤ 65%;
  * Creatinine clearance (CrCl) ≥ 30 mL/min to \< 45 mL/min calculated by the Cockcroft-Gault formula;
  * Moderate hepatic impairment with total bilirubin \> 1.5 to ≤ 3.0 × Upper Limit of Normal (ULN);
  * Other comorbidity that the physician judges to be incompatible with conventional intensive chemotherapy which must be reviewed and approved by the study medical monitor before study enrollment.

In addition, all subjects must meet the following criteria:

* If the subject is ≥ 75 years of age, then ECOG Performance Status must be 0-2.
* Subject must have adequate renal function as demonstrated by a CrCl ≥ 30 mL/min (calculated by the Cockcroft Gault formula or measured by 24-hour urine collection).
* Subject must have adequate liver function as demonstrated by:

  * Aspartate aminotransferase (AST) ≤ 3.0 × ULN\*
  * Alanine aminotransferase (ALT) ≤ 3.0 × ULN\*
  * Bilirubin ≤ 1.5 × ULN (subjects who are \< 75 years of age may have bilirubin of ≤ 3.0 × ULN)\* \*Unless considered to be due to leukemic organ involvement.
* Female subjects must be either postmenopausal defined as:

  * Age \> 55 years with no menses for ≥ 2 years without an alternative medical cause.
  * OR
  * Age ≤ 55 years with no menses for ≥ 12 months without an alternative medical cause AND a follicle-stimulating hormone level \> 40 IU/L;
  * OR
  * Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy); OR
* A woman of childbearing potential practicing at least 1 protocol specified method of birth control starting at Study Day 1 through at least 6 months after the last dose of study treatment.
* A woman of childbearing potential must have negative results for pregnancy test performed:

  * At Pretreatment with a serum sample obtained within 28 days prior to the first study treatment administration, and
  * Prior to dosing with urine sample obtained on Cycle 1 Day 1, if it has been \> 7 days since obtaining the serum pregnancy test results.
  * Subjects with borderline pregnancy tests at Pretreatment must have a serum pregnancy test ≥ 3 days later to document continued lack of a positive result.
* Male subjects who are sexually active, must agree, from Study Day 1 through at least 6 months after the last dose of study treatment, to practice protocol specified methods of contraception. Male subjects must agree to refrain from sperm donation from initial study treatment administration through at least 6 months after the last dose of study treatment.
* Subject must have a white blood cell count ≤ 25 × 10\^9/L. (Note: subjects who have undergone hydroxyurea administration or leukapheresis for therapeutic cytoreduction will be considered eligible).

Exclusion Criteria:

* Subject has ECOG Performance Status \> 3, regardless of age.
* Subject has known Human Immunodeficiency Virus (HIV) infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax). HIV testing will be performed at Pretreatment, if required per local guidelines or institutional standards.
* Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) as determined by the specified dose exploration
timeFrame: Up to 36 months
measure: Incidence of Adverse Events (AE) and Dose Limiting Toxicities (DLT)
timeFrame: Up to 36 months
Secondary outcomes:
measure: Proportion of subjects who have achieved CR, CRi, PR, and CRc (CR + CRi)
timeFrame: Up to 36 months
measure: Proportion of subjects who have achieved ORR
timeFrame: Up to 36 months
measure: Proportion of subjects who have achieved CR / CRi with MRD status
timeFrame: Up to 36 months
measure: AUCtau
timeFrame: Exploration: Cycle 1, Days 1 and 3: predose, 45 and 90 minutes (min), 4, 6, and 8 hours(hr); Days 2 and 4: 24 hr; Day 5: 48 hr; Cycle 2 Day 3: predose, 45 and 90 min, 4, 5, 6, and 8 hr; Day 4: 24 hr; Day 5: 48 hr (each cycle is 28-49 days)
measure: Maximum Plasma Concentration (Cmax)
timeFrame: Exploration:Cycle 1,Days 1 and 3:predose,45 and 90 minutes(min),4,6, and 8 hours (hr); Days 2 and 4:24 hr; Day 5:48 hr; Day 7:96 hr, Day 9:144 hr; Cycle 2 Day 3:predose,45 and 90 min,4,5,6, and 8 hr; Day 4:24 hr; Day 5:48 hr (each cycle is 28-49 days)
measure: Time to Cmax (Tmax)
timeFrame: Exploration:Cycle 1,Days 1 and 3:predose,45 and 90 minutes(min),4,6, and 8 hours (hr); Days 2 and 4:24 hr; Day 5:48 hr; Day 7:96 hr, Day 9:144 hr; Cycle 2 Day 3:predose,45 and 90 min,4,5,6, and 8 hr; Day 4:24 hr; Day 5:48 hr (each cycle is 28-49 days)
measure: Apparent Terminal Elimination Half-Life (t½)
timeFrame: Exploration:Cycle 1,Days 1 and 3:predose,45 and 90 minutes(min),4,6, and 8 hours (hr); Days 2 and 4:24 hr; Day 5:48 hr; Day 7:96 hr, Day 9:144 hr; Cycle 2 Day 3:predose,45 and 90 min,4,5,6, and 8 hr; Day 4:24 hr; Day 5:48 hr (each cycle is 28-49 days)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Atlanta
country: United States
facility: Blood & Marrow Transplant Group of Georgia
state: Georgia
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Dana Farber/ Brigham & Women's Cancer Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Charleston
country: United States
facility: MUSC Hollings Cancer Center
state: South Carolina
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
References: