A Trial of CPX-351 Lower Intensity Therapy (LIT) Plus Venetoclax as First Line Treatment for Subjects With AML
Study Details
Study Description
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). This study will comprise 2 phases: a Dose Escalation Phase and an Expansion Phase, in which all subjects will receive a combination of CPX-351 and venetoclax.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: CPX-351 and Venetoclax CPX-351 and Venetoclax will be administered over 28 day cycles |
Drug: CPX-351
CPX-351 will be administered on Days 1 and 3 of each cycle
Other Names:
Drug: Venetoclax
Venetoclax will be adminstered on Days 2 to 21 of each cycle
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Maximum Tolerated Dose (MTD) as determined by the specified dose escalation [Up to 30 months]
The MTD as determined by the specified dose escalation and MTD algorithm
- Incidence of Adverse Events (AE) and Dose Limiting Toxicities (DLT) [Up to 30 months]
The safety and tolerability of CPX-351 and venetoclax when given in combination based on the incidence of AEs and DLTs
Secondary Outcome Measures
- Proportion of subjects who have achieved CR, CRi, PR, and CRc (CR + CRi) [Up to 30 months]
Proportion of subjects who have achieved CR, CRi, PR, and CRc (CR + CRi) by the completion of treatment (up to 4 cycles of therapy)
- Proportion of subjects who have achieved ORR [Up to 30 months]
Proportion of subjects who have achieved ORR, defined as best response (CR + CRi + PR) by the completion of treatment (up to 4 cycles of therapy)
- Proportion of subjects who have achieved CR / CRi with MRD status [Up to 30 months]
Proportion of subjects who have achieved CR / CRi with MRD status (negative / positive) by the completion of treatment (up to 4 cycles of therapy)
- AUCtau [Up to 30 months]
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
- Maximum Plasma Concentration (Cmax) [Up to 30 months]
- Time to Cmax (Tmax) [Up to 30 months]
- Apparent Terminal Elimination Half-Life (t½) [Up to 30 months]
Eligibility Criteria
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 within 21 days 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 14 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 × 109/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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope | Duarte | California | United States | 91010 |
| 2 | Blood & Marrow Transplant Group of Georgia | Atlanta | Georgia | United States | 30342 |
| 3 | University of Kansas Medical Center | Kansas City | Kansas | United States | 66160 |
| 4 | Dana Farber/ Brigham & Women's Cancer Center | Boston | Massachusetts | United States | 02215 |
| 5 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
| 6 | Oregon Health & Science University | Portland | Oregon | United States | 97239 |
| 7 | MUSC Hollings Cancer Center | Charleston | South Carolina | United States | 29425 |
| 8 | Fred Hutchinson Cancer Research Center | Seattle | Washington | United States | 98109 |
Sponsors and Collaborators
- Jazz Pharmaceuticals
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CPX351-103