Clinical Trials /

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

NCT04512105

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pitavastatin in Combination With Venetoclax for Chronic Lymphocytic Leukemia or Acute Myeloid Leukemia
  • 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

Clinical Trial IDs

  • ORG STUDY ID: UCI 18-128
  • SECONDARY ID: 2020-5930
  • NCT ID: NCT04512105

Conditions

  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • AML, Adult
  • CLL
  • CLL, Relapsed
  • CLL, Refractory

Interventions

DrugSynonymsArms
PitavastatinLIVALO®Dose Level -1 (DL-1)
VenetoclaxVENCLEXTA®Dose Level -1 (DL-1)

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Dose Level -1 (DL-1)ExperimentalPatients 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.
  • Pitavastatin
  • Venetoclax
Dose Level 1 (DL1)ExperimentalPatients 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.
  • Pitavastatin
  • Venetoclax
Dose Level 2 (DL2)ExperimentalPatients 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.
  • Pitavastatin
  • Venetoclax

Eligibility 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 may not have received prior therapy aside from hydroxyurea.

          5. Patients with AML may not have received prior therapy aside from hydroxyurea

          6. Patients with acute promyelocytic leukemia are excluded

          7. Patients with known CNS involvement with leukemia are excluded

          8. 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.

          9. 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.

         10. Patients with a history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to PEN, PIT, or other statins are excluded.

         11. 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).

         12. 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.

         13. 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.

         14. Patients who are pregnant or breastfeeding are excluded.

         15. Patients who are unable to swallow pills are excluded.

         16. Patients having a malabsorption syndrome or other condition that precludes the
             oral/enteral route of administration are excluded

         17. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description:Responders are defined as individuals who either received a CR or PR. Responders = CR+PR.
Measure: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.
Safety Issue:
Description:Changes in safety status, such as Eastern Cooperative Oncology Group (ECOG), performance status, vital signs and laboratory assessments throughout treatment through the trial.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of California, Irvine

Trial Keywords

  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • AML
  • CLL

Last Updated

August 10, 2020