Clinical trial NCT03319901: Venetoclax and Chemotherapy as Frontline Therapy in Older Patients and Patients With Relapsed/Refractory ALL
Official title: A Phase Ib Study of the Combination of Venetoclax With Chemotherapy as Frontline Therapy in Older Patients and Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Leukemia
Keywords: Leukemia
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: AbbVie
First posted: 2017-10-24
Enrollment: 82
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 research study is studying a medication called Venetoclax and a chemotherapy regimen as a possible treatment for Acute Lymphoblastic Leukemia.

The drugs involved in this study are:

* Venetoclax
* Standard Chemotherapy (which includes cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, 6-mercaptopurine, etoposide, and cytarabine

Detailed description: This research study is a Phase I clinical trial, which tests the safety of an investigational drug and drug combination and also tries to define the appropriate dose of the investigational drug and drug combination to use for further studies. "Investigational" means that the drug and drug combination is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved Venetoclax for this specific disease, but it has been approved for other uses.

Venetoclax is an inhibitor of Bcl-2. Bcl-2 is critical for keeping cancer cells alive.

By inhibiting Bcl-2, venetoclax promotes cancer cell death. This drug is currently being used in other clinical trials for people with certain types of leukemia, lymphoma, and multiple myeloma. There is some evidence from those and other laboratory trials that venetoclax may kill cancer cells and cause tumors to shrink.

In this research study, the investigators are investigating how safe the combination of Venetoclax and standard chemotherapy is and how it affects this disease.. The participant will be given Venetoclax alone first and the standard chemotherapies will be given in combination. This study aims to provide information to help determine the dose of Venetoclax , in combination with standard chemotherapy, affects this disease the best and which dose is the safest.

Eligibility criteria: Inclusion Criteria:

* Patients with previously untreated acute lymphoblastic leukemia (B-cell or T-cell)
* Bone marrow involvement with ≥20% lymphoblasts
* Age ≥ 60 Years

OR

* Patients with relapsed or refractory acute lymphoblastic leukemia (B-cell or T-cell) defined as receiving one or more cytotoxic containing regimens
* Bone marrow involvement with ≥5% lymphoblasts
* Age ≥ 18 Years
* Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Refer to Appendix D)
* Adequate organ function

  * Serum total bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for patients with Gilbert's disease
  * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN, unless clearly due to disease involvement
  * Creatinine clearance \>50 mL/min (calculated according to institutional standards or using Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formula)
* Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug. Women of non- childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. Men who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug
* Patients or their legally authorized representative must provide written informed consent

Exclusion Criteria:

* Ph-positive ALL, Burkitt's leukemia/lymphoma, or lymphoblastic lymphoma
* Patient is pregnant or breastfeeding
* Patients with uncontrolled infection
* Hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV)
* Major surgery or radiation therapy within 4 weeks prior to the first study dose
* Systemic chemotherapy/radiotherapy/investigational therapy within 14 days (with the exception of hydroxyurea and/or dexamethasone, or one dose of cytarabine) prior to starting therapy
* Symptomatic or untreated leptomeningeal disease or spinal cord compression
* Patients with active heart disease (New York Heart Association (NYHA) class 3-4 as assessed by history and physical examination, unstable angina/stroke/myocardial infarction within the last 6 months)
* Patients with a cardiac ejection fraction (as measured by either Multi Gated Acquisition (MUGA) or echocardiogram (EKG)) \<40%
* History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years. Patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses)
* Concurrent use of warfarin
* Received Cytochrome P450 3A (CYP3A) inhibitors (such as fluconazole, ketoconazole, voriconazole, and clarithromycin) within 3 days of starting venetoclax; received strong CYP3A inducers (such as rifampin, rifabutin, phenytoin, carbamazepine, and St. John's Wort) within 3 days of starting venetoclax
* Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3 days prior to starting venetoclax
* Prior treatment with venetoclax
* Malabsorption syndrome or other conditions that preclude enteral route of administration
* Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study

Primary outcomes:
measure: Maximum Tolerated Dose
timeFrame: 2 years
Secondary outcomes:
measure: To Evaluate The Safety of the Combination
timeFrame: 2 years
measure: Complete Response
timeFrame: 2 years
measure: Progression Free Survival
timeFrame: 2 years
measure: Overall Survival
timeFrame: 2 years
measure: Minimal Residual Disease
timeFrame: 2 years
measure: Disease Free Survival
timeFrame: 2 years
measure: Change in expression of BCL-2 family proteins: BCL-2
timeFrame: 2 years
measure: Change in expression of BCL-2 family proteins: BCL-XL
timeFrame: 2 years
measure: Change in expression of BCL-2 family proteins: MCL-1 (anti-apoptotic)
timeFrame: 2 years
measure: Change in expression of BCL-2 family proteins: BCL-2 homology 3 (BH3)
timeFrame: 2 years
measure: Change in expression of BCL-2 family proteins: BIM
timeFrame: 2 years
measure: Change in expression of BCL-2 family proteins: BID
timeFrame: 2 years
measure: Change in expression of BCL-2 family proteins: BAD
timeFrame: 2 years
measure: Change in expression of BCL-2 family proteins: NOXA
timeFrame: 2 years
measure: Change in expression of BCL-2 family proteins: PUMA
timeFrame: 2 years
measure: Change in expression of BCL-2 family proteins: HRK (pro-apoptotic)
timeFrame: 2 years
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Intermountain LDS Hospital
state: Utah
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Marlise Luskin, MD, MSCE
role: PRINCIPAL_INVESTIGATOR
References: