Pitavastatin in Combination With Venetoclax for Chronic Lymphocytic Leukemia or Acute Myeloid Leukemia

February 6, 2024 updated by: Elizabeth Brem, MD, University of California, Irvine

A Phase 1 Open-Label, Dose Escalation Study of Pitavastatin in Combination With Venetoclax in Patients With Chronic Lymphocytic Leukemia or Acute Myeloid Leukemia

This is a phase I, dose-escalation, open-label clinical trial determining the safety and tolerability of adding Pitavastatin to Venetoclax in subjects with chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML). These are subjects who are newly diagnosed subjects with AML who are ineligible for intensive induction chemotherapy, relapsed/refractory CLL or newly diagnosed CLL.

Study Overview

Study Type

Interventional

Enrollment (Actual)

6

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • California
      • Orange, California, United States, 92868
        • Chao Family Comprehensive Cancer Center, University of California, Irvine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Pathologically confirmed AML or CLL, otherwise eligible for VEN-containing therapy at Screening

    1. Newly diagnosed patients with AML deemed ineligible for intensive induction chemotherapy (age 75 and older or < 75 years of age with comorbidities that preclude the use of intensive induction therapy) eligible to receive VEN at Screening. VEN may be combined with azacitidine or decitabine at the discretion of the treating Investigator.
    2. Relapsed/refractory CLL eligible to receive single-agent VEN or VEN in combination with rituximab at Screening.
    3. Newly-diagnosed CLL eligible to receive VEN in combination with obinatuzumab at Screening.
  2. Patients who have been receiving stable doses of VEN for at least 5 days prior to initiation of PIT add-on therapy.
  3. Age ≥ 18 years.
  4. Patients who are already on statins for dyslipidemias are eligible if their previous statin is stopped at least 72 hour prior to starting VEN-based therapy; administration of other statins is prohibited during the study.
  5. ECOG performance status ≤ 2 at baseline.
  6. Creatinine clearance 30 mL/min or higher; patients assigned to the highest dose level of PIT add-on therapy must have creatinine clearance 60 mL/min or higher.
  7. Liver Function tests within the following ranges:

    1. Aspartate aminotransferase (AST) ≤ 3.0 × ULN
    2. Alanine aminotransferase (ALT) ≤ 3.0 × ULN
    3. Bilirubin ≤ 1.5 × ULN (unless elevated bilirubin due to leukemic involvement in the liver or Gilbert's disease)
  8. Ability to understand and willingness to sign the informed consent.
  9. For the duration of the study treatment period and for at least 90 days following the last dose of study drug female of childbearing potential (FCBP) who are sexually active must agree to employ effective contraceptive methods. Effective contraceptive methods include use of hormonal contraception or an intrauterine device (IUD) by the female partner, or use of condoms by the male partner. An FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
  10. For the duration of the study treatment period and for at least 90 days following the last dose of study drug, male patients must agree to use effective contraceptive methods during sexual contact with a female of childbearing potential (FCBP) and must agree to refrain from semen or sperm donation during the same timeframe.

Exclusion Criteria:

  1. Patients who are receiving any investigational agents during the previous 30 days or at any time during the study.
  2. Patients who have previously received VEN.
  3. Patients who satisfy any of the contraindications for PIT.
  4. Patients with AML who received prior therapy other than hydroxyurea including those starting hypomethylating therapy for MDS after AML diagnosis.
  5. Patients with acute promyelocytic leukemia are excluded
  6. Patients with known CNS involvement with leukemia are excluded
  7. Patients with active hepatitis B (HBV) or hepatitis C (HCV) infection are excluded. Patients with prior HBV or HCV exposure and those on antiviral medications with negative HBV or HCV viral loads are eligible, as long as the antiretroviral drugs being used do not have significant CYP3A4 interactions.
  8. Patients with uncontrolled HIV are excluded. Patients with known HIV and undetectable viral loads are eligible as long as the antiretroviral drugs being used do not have significant CYP3A4 interactions.
  9. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to PEN, PIT, or other statins are excluded.
  10. Patients receiving are strong inhibitors or inducers of CYP3A4 within 7 days prior to initiation of VEN therapy are excluded. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. An exception to this is made for patients with AML who require anti-fungal therapy with appropriate dose reduction in VEN (see Section 5.10.2.3).
  11. Patients who have consumed grapefruit, grapefruit juice or Seville oranges within 72 hours of initiation of VEN therapy. Consumption of grapefruit, grapefruit juice, Seville oranges, or orange marmalade should be avoided for the duration of the study, as these affect CYP3A4 activity.
  12. Patients with certain uncontrolled intercurrent illness are excluded. These include, but are not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illnesses, or social situations that would limit compliance with study requirements.
  13. Patients who are pregnant or breastfeeding are excluded.
  14. Patients who are unable to swallow pills are excluded.
  15. Patients having a malabsorption syndrome or other condition that precludes the oral/enteral route of administration are excluded
  16. Patients with an active concurrent malignancy other than CLL or AML are excluded. Patients with a history of definitively treated prior malignancy with low risk of recurrence, skin cancers that have been excised, or on prolonged adjuvant hormonal therapy (ie, for breast or prostate cancer) but are otherwise considered in remission are eligible.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Dose Level -1 (DL-1)

Patients receive Pitavastatin (PIT) 1 mg PO daily. For CLL patients, they will also receive stabilized Venetoclax (VEN) 400mg PO daily. For AML patients, they will VEN mg PO daily when dosing in combination with azacitidine or decitabine.

The 1 mg/day dose level will be held in reserve to allow dose reduction in those patients who cannot tolerate DL1.

Given PO
Other Names:
  • VENCLEXTA®
Given PO
Other Names:
  • LIVALO®
Experimental: Dose Level 1 (DL1)

Patients receive Pitavastatin (PIT) 2 mg PO daily. For CLL patients, they will also receive stabilized Venetoclax (VEN) 400mg PO daily. For AML patients, they will VEN mg PO daily when dosing in combination with azacitidine or decitabine.

This is the starting dose level for the study.

Given PO
Other Names:
  • VENCLEXTA®
Given PO
Other Names:
  • LIVALO®
Experimental: Dose Level 2 (DL2)

Patients receive Pitavastatin (PIT) 4 mg PO daily. For CLL patients, they will also receive stabilized Venetoclax (VEN) 400mg PO daily. For AML patients, they will VEN mg PO daily when dosing in combination with azacitidine or decitabine.

If DL1 is well tolerated, the next cohort will progress to this dose level.

Given PO
Other Names:
  • VENCLEXTA®
Given PO
Other Names:
  • LIVALO®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose for PIT administered with VEN-containing Standard of Care (SOC) regimens
Time Frame: From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Determination of the maximum tolerated dose (MTD) will be utilized to evaluate the safety and tolerability of adding to PIT to treatment with stable doses of VEN ± anti-CD20 antibodies (patients with CLL) or VEN with hypomethylating agents (patients with AML).
From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Recommended Phase 2 Dose for PIT administered with VEN-containing SOC regimens
Time Frame: From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Determination of the recommended Phase 2 dose (RP2D) will be utilized to evaluate the safety and tolerability of adding to PIT to treatment with stable doses of VEN ± anti-CD20 antibodies (patients with CLL) or VEN with hypomethylating agents (patients with AML).
From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Identifying Dose Limiting Toxicities (DLTs) for PIT administered with VEN-containing SOC regimens
Time Frame: From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
To evaluate the safety and tolerability of administering PIT in combination with VEN-containing SOC in patients with AML or CLL .
From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Identifying overall Adverse Event Profile of PIT when given with VEN-containing SOC regimens
Time Frame: From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
To evaluate the adverse events are based on the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0.
From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Complete Response Rate
Time Frame: From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Primary efficacy endpoint is the complete response rate of subjects who receive PIT when given with VEN-containing SOC regimens. The 2018 International Working Group for Chronic Lymphocytic Leukemia (iwCLL) and 2017 European LeukemiaNet (ELN) definitions of Complete Response (CR) will be utilized to determine the CR rate.
From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Partial Response Rates
Time Frame: From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Secondary efficacy endpoints are the rates for the other response categories of subjects who receive PIT when given with VEN-containing SOC regimens. The 2018 International Working Group for Chronic Lymphocytic Leukemia (iwCLL) and 2017 European LeukemiaNet (ELN) definitions of Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) will be utilized to determine the rates for each of these categories.
From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Stable Disease Rates
Time Frame: From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Secondary efficacy endpoints are the rates for the other response categories of subjects who receive PIT when given with VEN-containing SOC regimens. The 2018 International Working Group for Chronic Lymphocytic Leukemia (iwCLL) and 2017 European LeukemiaNet (ELN) definitions of Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) will be utilized to determine the rates for each of these categories.
From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Progressive Disease Rates
Time Frame: From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Secondary efficacy endpoints are the rates for the other response categories of subjects who receive PIT when given with VEN-containing SOC regimens. The 2018 International Working Group for Chronic Lymphocytic Leukemia (iwCLL) and 2017 European LeukemiaNet (ELN) definitions of Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) will be utilized to determine the rates for each of these categories.
From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Percentage of Responders
Time Frame: From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Responders are defined as individuals who either received a CR or PR. Responders = CR+PR.
From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Number of Participants with Abnormal Laboratory Values and/or Adverse Events that Are Related to Treatment
Time Frame: From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.
Changes in safety status, such as Eastern Cooperative Oncology Group (ECOG), performance status, vital signs and laboratory assessments throughout treatment through the trial.
From the start date of treatment until 30 days after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 2 years.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Composite of PK parameters of VEN and PIT summarized by PIT dose level
Time Frame: Samples will be collected at the following timepoints: Pre-VEN dose during screening, Cycle 1 Day 1 Pre-VEN and PIT dose, Cycle 1 Day 1 Post dose sampling at 1, 2, 4, 8, 24 hours after first PIT dose. Each cycle is 28 days.
Change in PK parameters from baseline to Cycle 1 to determine if concomitant administration of PIT affects concentrations of VEN when given in combination with PIT.
Samples will be collected at the following timepoints: Pre-VEN dose during screening, Cycle 1 Day 1 Pre-VEN and PIT dose, Cycle 1 Day 1 Post dose sampling at 1, 2, 4, 8, 24 hours after first PIT dose. Each cycle is 28 days.
Composite of dynamic BH3 profiling in priming of ex vivo AML and CLL specimens
Time Frame: Samples will be collected for BH3 profiling at the following timepoints: prior to initiation of VEN treatment, Cycle 1 Day 1 Pre-PIT dose and predose Cycle 1 Day 2. Each cycle is 28 days.
BH3 profiling on pretreatment and post-treatment bloods samples to assess whether add on treatment with PIT increases apoptotic priming. In dynamic BH3 profiling, the degree of mitochondrial outer membrane permeabilization (MOMP) after exposure to drug is compared to the untreated baseline to quantify the change in priming or induced by exposure to a drug.
Samples will be collected for BH3 profiling at the following timepoints: prior to initiation of VEN treatment, Cycle 1 Day 1 Pre-PIT dose and predose Cycle 1 Day 2. Each cycle is 28 days.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Elizabeth Brem, MD, Chao Family Comprehensive Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 2, 2020

Primary Completion (Actual)

April 6, 2023

Study Completion (Estimated)

June 1, 2024

Study Registration Dates

First Submitted

July 3, 2020

First Submitted That Met QC Criteria

August 10, 2020

First Posted (Actual)

August 13, 2020

Study Record Updates

Last Update Posted (Actual)

February 8, 2024

Last Update Submitted That Met QC Criteria

February 6, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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