Acute Myeloid Leukemia
Conditions
Keywords
CPX-351, Vyxeos, Venetoclax, Unfit
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.
Interventions
DRUGCPX-351
CPX-351 will be administered on Days 1 and 3 of each cycle
DRUGVenetoclax
Venetoclax will be adminstered on Days 2 to 21 of each cycle
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) as determined by the specified dose exploration | Up to 36 months | The Recommended Phase 2 Dose (RP2D) as determined by an assessment of all safety data from the Dose Exploration Phase. |
| Incidence of Adverse Events (AE) and Dose Limiting Toxicities (DLT) | Up to 36 months | The safety and tolerability of CPX-351 and venetoclax when given in combination based on the incidence of AEs and DLTs |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of subjects who have achieved ORR | Up to 36 months | Proportion of subjects who have achieved ORR, defined as best response (CR + CRi + PR) at any time while receiving study treatment. |
| Proportion of subjects who have achieved CR / CRi with MRD status | Up to 36 months | Proportion of subjects who have achieved CR / CRi with MRD status (negative / positive) at any time while receiving study treatment. |
| Apparent Terminal Elimination Half-Life (t½) | 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) | — |
| Maximum Plasma Concentration (Cmax) | 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) | — |
| Time to Cmax (Tmax) | 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) | — |
| AUCtau | 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) | Area under the plasma concentration time curve from time 0 to the time of the next dosing during a 48 hour interval at the steady-state of CPX-351 PK |
| Proportion of subjects who have achieved CR, CRi, PR, and CRc (CR + CRi) | Up to 36 months | Proportion of subjects who have achieved CR, CRi, PR, and CRc (CR + CRi) at any time while receiving study treatment. |
Countries
United States
Outcome results
None listed