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

• ClinicalTrials.gov Identifier: NCT04512105
• Recruitment Status: Recruiting
• First Posted: August 13, 2020
• Last Update Posted: March 29, 2021
• Sponsor: University of California, Irvine
• Collaborator: United States Department of Defense
• Information provided by (Responsible Party): Elizabeth Brem, MD, University of California, Irvine

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia; Chronic Lymphocytic Leukemia; AML, Adult; CLL; CLL, Relapsed; CLL, Refractory	Drug: Pitavastatin; Drug: Venetoclax	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Open-Label, Dose Escalation Study of Pitavastatin in Combination With Venetoclax in Patients With Chronic Lymphocytic Leukemia or Acute Myeloid Leukemia
• Actual Study Start Date: December 2, 2020
• Estimated Primary Completion Date: April 20, 2022
• Estimated Study Completion Date: June 1, 2022

Arms and Interventions

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.	Drug: Pitavastatin; Given PO; Other Name: LIVALO®; Drug: Venetoclax; Given PO; Other Name: VENCLEXTA®
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.	Drug: Pitavastatin; Given PO; Other Name: LIVALO®; Drug: Venetoclax; Given PO; Other Name: VENCLEXTA®
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.	Drug: Pitavastatin; Given PO; Other Name: LIVALO®; Drug: Venetoclax; Given PO; Other Name: VENCLEXTA®

Outcome Measures

Primary Outcome Measures :

1. 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).
2. 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).
3. 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 .
4. 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.
5. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.

Other Outcome Measures:

1. 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.
2. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Chao Family Comprehensive Cancer Center University of California, Irvine; 1-877-827-7883; ucstudy@uci.edu

Contact: University of California Irvine Medical

Locations

United States, California

Chao Family Comprehensive Cancer Center, University of California, Irvine; Recruiting

Orange, California, United States, 92868

Contact: Elizabeth Brem, MD 877-827-8839 ucstudy@uci.edu

Sponsors and Collaborators

University of California, Irvine

United States Department of Defense

Investigators

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

More Information

• Responsible Party: Elizabeth Brem, MD, HS Assistant Clinical Professor, University of California, Irvine
• ClinicalTrials.gov Identifier: NCT04512105
• Other Study ID Numbers: UCI 18-128 [HS# 2020-5930]; 2020-5930 ( Other Identifier: University of California, Irvine ); CDMRP-CA190644 ( Other Identifier: Department of Defense )
• First Posted: August 13, 2020
• Last Update Posted: March 29, 2021
• Last Verified: March 2021

• 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

Keywords provided by Elizabeth Brem, MD, University of California, Irvine:

Acute Myeloid Leukemia; Chronic Lymphocytic Leukemia; AML; CLL

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Venetoclax; Pitavastatin; Antineoplastic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Lipid Regulating Agents