Combination Merestinib and LY2874455 for Patients With Relapsed or Refractory Acute Myeloid Leukemia

NCT03125239 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 17-099
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 2

Brief Summary

This research study is studying a combination of two targeted therapies as a possible treatment for acute myeloid leukemia (AML) that has relapsed after initial treatment or did not fully respond. The name of the study interventions involved in this study are:

• Merestinib
• LY2874455

Conditions

Relapsed Adult Acute Myeloid Leukemia; Refractory Adult Acute Myeloid Leukemia

Keywords

Refractory Adult Acute Myeloid Leukemia; Relapsed Adult Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• MTD of LY2874455 and Merestinib

  Dose-escalation will follow a standard 3+3 design exploring 3 dose levels of LY2874455 with a steady dose of Merestinib. We will escalate to next dose cohort if 0/3 or 1/6 participants have a DLT during the first cycle of therapy. If the rate of dose limiting toxicity (DLT) exceeds 30%, it is less likely that the dose of LY2874455 will be escalated.

  35 Days

Secondary Outcomes (6)

• Best Overall response

  Up to 1 year

• Duration of Remission

  Up to 1 year

• Progression Free Survival

  Up to 1 year

• Overall Survival

  Up to 1 year

• PK of Merestinib and LY2874455 in AML during the dose escalation part of the study: AUC

  35 days

Study Arms (1)

Merestinib and LY2874455

EXPERIMENTAL

Patients who fulfill eligibility criteria will be entered into the trial to receive Merestinib and LY2874455. After the screening procedures confirm participation in the research study: * The investigators are looking for the highest dose of the combination of study drugs that can be administered safely without severe or unmanageable side effects in participants that have AML, not everyone who participates in this research study will receive the same dose of the study drug. The dose given will depend on the number of participants who have been enrolled in the study prior and how well the dose was tolerated. * Merestinib * LY2874455

Drug: Merestinib; Drug: LY2874455

Interventions

Merestinib DRUG

Oral, once a day, Merestinib Only- Lead in period on week. The followed by cycles on combination therapy with Merestinib and LY2874455 (28 days long)

Also known as: LY2801653

Merestinib and LY2874455

LY2874455 DRUG

This will be followed by cycles of combination therapy with merestinib and LY2874455. Each of these cycles are 28 days long. • LY2874455 will be taken by mouth twice a day. You may take LY2874455 twice daily for 14 days, 21 days, or 28 days each cycle depending on the dose level you are assigned.

Merestinib and LY2874455

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have pathologically confirmed relapsed or refractory acute myeloid leukemia (AML) or secondary AML following IWG criteria \[40\].
• For subjects with relapsed AML: evidence of ≥ 5% blasts in the bone marrow or development of extramedullary disease who relapse after:
• Allogeneic hematopoietic stem cell transplant, or
• A minimum of one cycle of standard cytotoxic chemotherapy or two cycles of any hypomethylating agent-based therapy
• For subjects with refractory AML: a minimum of 2 prior induction regimens (example: patients who receive 7+3 followed by 5+2 would count as one induction regimen) or a minimum of two cycles of any hypomethylating agent-based therapy.
• For subjects with secondary AML: untreated secondary AML, must have been previously treated for myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN) or MDS/MPN (MDS/MPN) overlap syndrome.
• No limit to number of prior therapies.
• Patients are considered to have failed available therapies or to be ineligible for or to not be interested in intensive chemotherapies, including allogeneic hematopoietic stem cell transplantation.
• Patients with a history of allogeneic stem cell transplantation are eligible for study participation provided the transplant was \> 100 days prior to study enrollment. Patients must not have active graft versus host disease other than grade 1 skin involvement.
• Age 18 and older.
• ECOG performance status ≤2 (see Appendix A).
• Participants must have normal organ and marrow function as defined below:
• Direct bilirubin within ≤ 1.5 times the institutional upper limit of normal (ULN). For patients with known Gilbert Syndrome, or if the elevation is believed to be leukemia related, the cut-off of ≤ 3.0 times the institutional ULN is allowable.
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN, unless believed to be leukemia related then ≤ 5 x ULN is allowed.
• Serum creatinine ≤ 2.0 x ULN

You may not qualify if:

• Participants who have had radiotherapy within 2 weeks, with the exception of localized radiotherapy to palliate extramedullary leukemia where no washout is required.
• Participants who have had chemotherapy within 2 weeks or 5 half-lives (whichever is longer) from the last dose of chemotherapy prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. Hydroxyurea is allowed per treating investigator. IT chemotherapy prophylaxis is permitted.
• Participants who are receiving any other investigational agents, with the exception of topical or ophthalmologic therapies for mild graft versus host disease which are permitted.
• Participants with known CNS leukemia involvement should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• Individuals with other active malignancies that require concurrent chemotherapy are ineligible. Hormone therapy is allowed.
• Subject has a known gastrointestinal disorder that in the opinion of the treating investigator is concerning for malabsorption of oral medications.
• Subject is unable to swallow pills.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients with current or history of NYHA class III or IV cardiac disease, myocardial infarction with past 6 months, or unstable arrhythmia will be ineligible for study.
• Pregnant women are excluded from this study because Merestinib and LY2874455 have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Merestinib and LY2874455, breastfeeding should be discontinued if the mother is treated with Merestinib and LY2874455.
• HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Merestinib and LY2874455. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
• Subjects with known active HBV or HCV (cannot have an elevated viral load of HBV or HCV if known history) are ineligible

Sponsors & Collaborators

• Jacqueline Garcia, MD: lead
• Eli Lilly and Company: collaborator

Study Sites (2)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

merestinib; 2-(4-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3yl)vinyl)-1H-pyrazol-1-yl)ethanol

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Jacqueline S. Garcia, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Model Details: open-label phase 1 study using a 3+3 design with planned dose escalation

Study Record Dates

• First Submitted: April 17, 2017
• First Posted: April 24, 2017
• Study Start: August 10, 2017
• Primary Completion: June 1, 2020
• Study Completion: June 1, 2020
• Last Updated: June 30, 2020

Record last verified: 2020-06

Locations

US (2)