Crenolanib in Combination With Sorafenib in Patients With Refractory or Relapsed Hematologic Malignancies

NCT ID: NCT02270788

Last Updated: 2017-10-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-02
• Study Completion Date: 2016-10-17

Brief Summary

PRIMARY OBJECTIVE:

This is a pilot study to characterize the toxicity profile, to determine the maximum tolerated dose of the combination of crenolanib and sorafenib, and to determine the feasibility of administering these drugs in patients with relapsed or refractory hematologic malignancies, including acute myeloid leukemia (AML), AML with prior myelodysplastic syndrome (MDS), and myeloperoxidase (MPO)-positive mixed phenotype acute leukemia with FLT3-internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations.

The study will include two phases:

• The dose-escalation phase will characterize the dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of crenolanib when given in combination with sorafenib.
• The dose-expansion cohort will further assess the safety and explore the efficacy of this combination.

Detailed Description

Each course of therapy will be 28 days (±5 days), unless disease progression is seen while on the combination of crenolanib with sorafenib. Patients may receive subsequent courses (up to a total of 365 days) if there is no disease progression or unacceptable toxicity.

In Day 1 of Course 1, crenolanib is given once in the morning followed by characterization of the pharmacokinetic profile over the following 24-hour period. Starting with day 2 of Course 1, crenolanib will be given 3 times per day through day 28. On Days 8 to 28 of Course 1, sorafenib will be given once per day. Inter-patient dose escalation or de-escalation of crenolanib will be performed based on tolerability and toxicity.

Response will be assessed on days 8 and at end of course. If disease progresses prior to day 8, then sorafenib can be given before day 8.

In subsequent courses (up to 365 days), crenolanib and sorafenib are given on days 1 through 28. The treating physician may increase or decrease the sorafenib dose and frequency of administration per the trial's dosing table on the basis of effects and tolerability. If necessary, the crenolanib dose can be decreased per protocol.

Maintenance therapy must start no sooner than 30 days and no later than 120 days after hematopoietic stem cell therapy (HSCT). Single agent crenolanib will start at the last dose tolerated prior to HSCT. Crenolanib maintenance can be given for up to 365 days and additional therapy can be provided after discussion after discussion with the PI, in patients who continue to benefit after 1 year.

Conditions

Acute Myeloid Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Study Participants

All participants who consent and are enrolled on the study.

Interventions: Crenolanib, sorafenib, triple intrathecal chemotherapy (methotrexate, hydrocortisone and cytarabine with leucovorin).

Group Type: EXPERIMENTAL

Crenolanib

Intervention Type: DRUG

Day 1 of Course 1: once followed by pharmacokinetic analysis. Days 2-28 of cycle 1: 3 times per day Crenolanib dose will not be adjusted unless the participant experiences side effects.

All subsequent courses: 3 times per day on Days 1-28. At least 50% of participants in each dose level must be ≤ 18 years old.

Sorafenib

Intervention Type: DRUG

Days 8-28 of course 1: given orally once each day.

All subsequent courses: given orally on days 1-28 once per day

This is a dose-finding study for the use of sorafenib in combination with crenolanib. Different doses will be given to several participants, with the first participants receiving a lower dose than typically used in children as a single agent. If the drug does not cause serious side effects, it will be given to other study participants at a higher dose. If side effects occur, the dose will be lowered.

methotrexate, hydrocortisone and cytarabine with leucovorin

Intervention Type: DRUG

Triple IT therapy includes methotrexate, hydrocortisone and cytarabine with leucovorin rescue given on day 8. All participants will receive one IT chemotherapy on Day 8 of the first cycle. If they do not have leukemia cells in their spinal fluid, they will receive only one IT chemotherapy per cycle. If leukemia cells are present in their spinal fluid, they will receive IT chemotherapy weekly during the course. Triple IT therapy will be repeated on Day 1 of Cycle 2 and with each subsequent cycle in all participants.

Interventions

Crenolanib

Day 1 of Course 1: once followed by pharmacokinetic analysis. Days 2-28 of cycle 1: 3 times per day Crenolanib dose will not be adjusted unless the participant experiences side effects.

All subsequent courses: 3 times per day on Days 1-28. At least 50% of participants in each dose level must be ≤ 18 years old.

Intervention Type: DRUG

Sorafenib

Days 8-28 of course 1: given orally once each day.

All subsequent courses: given orally on days 1-28 once per day

This is a dose-finding study for the use of sorafenib in combination with crenolanib. Different doses will be given to several participants, with the first participants receiving a lower dose than typically used in children as a single agent. If the drug does not cause serious side effects, it will be given to other study participants at a higher dose. If side effects occur, the dose will be lowered.

Intervention Type: DRUG

methotrexate, hydrocortisone and cytarabine with leucovorin

Triple IT therapy includes methotrexate, hydrocortisone and cytarabine with leucovorin rescue given on day 8. All participants will receive one IT chemotherapy on Day 8 of the first cycle. If they do not have leukemia cells in their spinal fluid, they will receive only one IT chemotherapy per cycle. If leukemia cells are present in their spinal fluid, they will receive IT chemotherapy weekly during the course. Triple IT therapy will be repeated on Day 1 of Cycle 2 and with each subsequent cycle in all participants.

Intervention Type: DRUG

Other Intervention Names

CP-868,596; IND 112201; Sorafenib tosylate; BAY-43-9006; Nexavar®; Triple IT chemotherapy

Eligibility Criteria

Inclusion Criteria

• Participant has a relapsed or refractory hematologic malignancy (with any measurable disease) with FLT3-ITD or TKD mutations and one of the following diagnoses:

• Acute myeloid leukemia (AML)
• AML with prior myelodysplastic syndrome (MDS)
• Myeloperoxidase (MPO)-positive mixed phenotype acute leukemia
• Participant's disease has relapsed after, is refractory to induction and/or salvage therapy, or has relapsed after hematopoietic stem cell transplant (HSCT).
• Participant disease tested positive for FLT3-ITD or -TKD within 60-day screening period.
• Participant's age is 1 to 25 years, inclusive (St. Jude participants must be aged 1 to 25 years, inclusive).
• Karnofsky or Lansky performance score is > 60%. The Lansky performance score should be used for participants < 16 years and the Karnofsky performance score for participants ≥ 16 years.
• Adequate organ function defined as:

• Bilirubin ≤1.5 x upper limit of normal (ULN)
• ALT ≤ 3 x ULN and AST ≤ 3 x ULN
• Serum creatinine ≤1.5 x ULN
• Participant must have recovered from the acute side effects of all prior anti-cancer therapy, and:

• At least 2 weeks have elapsed since prior systemic cytotoxic chemotherapy (except intrathecal chemotherapy, hydroxyurea, low-dose cytarabine, and/or low dose maintenance therapy such as vincristine, mercaptopurine, methotrexate or glucocorticoids), and
• If the participant received a prior allogeneic HSCT, at least 30 days have elapsed and there is no evidence of clinically significant graft versus host disease requiring treatment and/or have > grade 2 persistent non-hematologic toxicity related to a transplant

• Patient must have received crenolanib on this protocol prior to HSCT to continue on to maintenance.
• Patient must be within 30 - 120 days after hematopoietic stem cell transplant (HSCT).
• Response to previous treatment on this protocol: at least resistant disease with clinical benefit or better response.
• Patient is off or on a stable dose of immunosuppressive drugs for management or prophylaxis of graft-versus-host-disease (GVHD) (defined as no escalation of therapy for GVHD) within 14 days prior to starting crenolanib.
• Patient must have recovered from acute side effects of HSCT, defined as having <Grade 2 non-hematological toxicity related to the transplant (exceptions are alopecia and other non-acute toxicities).
• Adequate hematopoietic recovery (ANC >500/mm^3 and platelet count >50,000/mm^3)
• Research participant or legal guardian/representative is able and willing to give written informed consent.

Exclusion Criteria

• Concurrent chemotherapy, or targeted anti-cancer agents, other than hydroxyurea, low-dose cytarabine, intrathecal therapy and/or low dose maintenance therapy such as vincristine, mercaptopurine, methotrexate or glucocorticoids.
• Patient with concurrent severe and/or uncontrolled medical conditions that, in the opinion of the investigator, may impair participation in the study or the evaluation of safety and/or efficacy.
• Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as hepatitis C antibody-positive).
• Prior crenolanib treatment for a non-leukemic indication.
• Major surgical procedures within 14 days of Day 1 administration of crenolanib.
• Pregnant or lactating (female participant of childbearing potential must have negative serum or urine pregnancy test required within 7 days prior to start of treatment).
• Male or female participant of reproductive potential must agree to use appropriate methods of contraception for the duration of study treatment and for at least 30 days after last dose of protocol treatment
• Inability or unwillingness or research participant or legal guardian/representative to give written informed consent.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 39 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Arog Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

Ohio State University

OTHER

Sponsor Role: collaborator

St. Jude Children's Research Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hiroto Inaba, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

St. Jude Children's Research Hospital

Locations

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Countries

United States

Related Links

http://www.stjude.org

St. Jude Children's Research Hospital

http://stjude.org/protocols

Clinical Trials Open at St. Jude

Other Identifiers

NCI-2014-01784

Identifier Type: REGISTRY

Identifier Source: secondary_id

RELHEM2

Identifier Type: -

Identifier Source: org_study_id