Venetoclax and Lintuzumab-Ac225 in AML Patients

Sponsor

Actinium Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03867682

Collaborator

(none)

Enrollment

Locations

Arm

35.5

Anticipated Duration (Months)

7.6

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study is a multicenter, open label Phase I/II trial.

To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 added to venetoclax for patients with CD33 positive relapsed/refractory AML. (Phase 1 portion)
To assess the percentage of patients with CR, CRh, or Overall Response (CR + CRh), up to 6 months after the start of treatment without receiving other AML therapies. (Phase 2 portion)

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Relapsed Adult AML	Biological: Lintuzumab-Ac225 Drug: Venetoclax Drug: Spironolactone	Phase 1/Phase 2

Detailed Description

The study is a multicenter, open label Phase I and Phase II trial combining lintuzumab-Ac225 with venetoclax in patients who have relapsed or refractory AML.

The Phase I portion is a dose-finding study which will enroll at least three patients at each dose level. Patients in a dose level will be observed for a minimum of 4 weeks before dose escalation occurs. There is no dose escalation for any individual patient.

The Phase II portion of the study will enroll patients at the MTD dose level of lintuzumab-Ac225 as determined in the Phase I portion of the study. The goal of the Phase II portion will be to further characterize the safety and efficacy of the MTD dose of lintuzumab-Ac225.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

38 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Study of Venetoclax and Lintuzumab-Ac225 in Patients With Refractory or Relapsed AML

Actual Study Start Date :

Jan 15, 2020

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Jan 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase I and Phase II Lintuzumab-Ac225 administered on Day 5 of each cycle for four cycles (unless in the 0.5 μCi/kg or 0.25 μCi/kg cohorts, where there is a potential for an additional four cycles, pending PI and Medical Monitor review). Venetoclax taken on Days 1-21 of each cycle for up to 12 cycles. Each cycle is 28 days, with a potential to expand to 42 days to allow for full hematologic recovery.	Biological: Lintuzumab-Ac225 In the Phase I, patients will be enrolled into the following dose escalation cohorts: 0.50 μCi/kg, 1.0 μCi/kg, and 1.5 μCi/kg. If the 0.50 μCi/kg dose is determined to exceed the MTD, a 0.25 μCi/kg dose will be explored. Other Names: Actimab Drug: Venetoclax 400 mg daily will be taken orally on Days 1-21 of a 28-day cycle. There will be a ramp up of venetoclax dosing in the first cycle, with 100 mg administered on Day 1, 200 mg on Day 2, and 400 mg on Day 3 and Day 4 and later. Patients on antifungal azoles should receive one-half these doses, up to a maximum of 200 mg of venetoclax. Other Names: Venclexta Drug: Spironolactone 25 mg by mouth daily, administered on Cycle 1 Day 15 and continued for 12 months after the subject's last treatment with lintuzumab-Ac225. Other Names: Aldactone

Arm

Intervention/Treatment

Experimental: Phase I and Phase II

Lintuzumab-Ac225 administered on Day 5 of each cycle for four cycles (unless in the 0.5 μCi/kg or 0.25 μCi/kg cohorts, where there is a potential for an additional four cycles, pending PI and Medical Monitor review). Venetoclax taken on Days 1-21 of each cycle for up to 12 cycles. Each cycle is 28 days, with a potential to expand to 42 days to allow for full hematologic recovery.

Biological: Lintuzumab-Ac225

In the Phase I, patients will be enrolled into the following dose escalation cohorts: 0.50 μCi/kg, 1.0 μCi/kg, and 1.5 μCi/kg. If the 0.50 μCi/kg dose is determined to exceed the MTD, a 0.25 μCi/kg dose will be explored.

Other Names:

Actimab

Drug: Venetoclax

400 mg daily will be taken orally on Days 1-21 of a 28-day cycle. There will be a ramp up of venetoclax dosing in the first cycle, with 100 mg administered on Day 1, 200 mg on Day 2, and 400 mg on Day 3 and Day 4 and later. Patients on antifungal azoles should receive one-half these doses, up to a maximum of 200 mg of venetoclax.

Other Names:

Venclexta

Drug: Spironolactone

25 mg by mouth daily, administered on Cycle 1 Day 15 and continued for 12 months after the subject's last treatment with lintuzumab-Ac225.

Other Names:

Aldactone

Outcome Measures

Primary Outcome Measures

Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225 [Cycle 1, up to 48 days]
To determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 added to venetoclax for patients with CD33 positive relapse/refractory AML.
Phase II: Overall Response (CR + CRh + CRi) [Up to 6 months]
To assess the percentage of patients with CR, CRh, CRi or Overall Response (CR + CRh + CRi), up to 6 months after the start of treatment without receiving other AML therapies.

Secondary Outcome Measures

Phase I: Overall Response [Up to 6 months]
Number of patients who's overall response is CR, CRh, or CRi
Phase I and II: OS [End of 6 months, 12 months, 2 years]
Number of patients who died
Phase I and II: DFS [End of 6 months, 12 months, 2 years]
Disease-free survival
Phase I and II: Evaluate incidence of AEs and SAEs [Through study completion, up to 2 years]
Rate of AEs and SAEs, including infusion-related reactions
Phase I and II: Evaluate BH3 priming assay results [Completion of Cycle 1, estimated 1 month]
Summary of assay results
Phase I and II: MRD status [From date of first dose until the date of first documented response, first assessment at 6 months]
Number of patients who are MRD negative
Phase I and II: Lab abnormalities (other than hematologic indices) [Through study completion, up to 2 years]
Summary of rate of Grade 3/4 lab abnormalities

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Refractory or relapsed AML which will include:
Refractory disease will be defined as at least 1 prior treatment with no remission.
Relapsed disease will be defined as 5% or more blasts in bone marrow seen after remission.
Patients with AML arising from myelodysplastic syndromes (including CMML) or myeloproliferative neoplasms (secondary AML, ts-AML) are also eligible.
Circulating blast count ≤ 200/μL within 10 days prior to first cycle of treatment. Hydroxyurea should be used to keep the peripheral blast count ≤ 200/μL until the first day of protocol treatment, to the extent that this is possible
ECOG ≤ 2
Estimated creatinine clearance ≥ 50 mL/min
AST and ALT ≤ 3.0 x ULN
Bilirubin ≤ 3.0 x ULN

Exclusion Criteria:

Active CNS Leukemia.
Known HIV infection or known hepatitis B or hepatitis C infection (with a detectable viral load).
Participant has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment.
Secondary refractory AML (e.g., treated for current relapse without achieving remission);

With the exception that single agent FLT3 inhibitors, IDH1/IDH2 inhibitors are allowed for current relapse without achieving remission.

Have received prior radiation to maximally tolerated levels to any critical normal organ.
Clinically significant cardiac disease.
Active, uncontrolled serious infection.
Have other non-myeloid malignancy within 2 years of entry (with exceptions).
Psychiatric disorder that would preclude study participation
Previous solid organ transplant (prior treatment with SCT is allowed but not if patient has GVHD or is still receiving immunosuppression/GVHD therapy).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California	Los Angeles	California	United States	90095
2	University of Louisville	Louisville	Kentucky	United States	40202
3	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
4	Weill Cornell Medicine	New York	New York	United States	10021
5	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109