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

NCT02270788 | Completed Phase 1 FDA Drug

• 2 other identifiers: RELHEM2NCI-2014-01784
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Dose-limiting toxicity (DLT)

  Any participant who experiences DLT at any time during cycle 1 of protocol therapy is considered evaluable for toxicity. Participants without DLT and can be followed for 28 days are also considered evaluable for toxicity. Participants who are not evaluable for toxicity (such as those removed early from therapy to start alternate therapy) at a given dose level will be replaced.

  Through Day 28 of Course 1

• Maximum tolerated dose (MTD)

  The MTD is empirically defined as the highest dose level at which six participants have been treated with at most one participant experiencing a DLT and the next higher dose has been determined to be too toxic. If the lowest dose level studied is too toxic or the highest dose level studied is considered safe, the MTD will not have been considered estimated.

  Through Day 28 of Course 1

Study Arms (1)

Study Participants

EXPERIMENTAL

All participants who consent and are enrolled on the study. Interventions: Crenolanib, sorafenib, triple intrathecal chemotherapy (methotrexate, hydrocortisone and cytarabine with leucovorin).

Drug: Crenolanib; Drug: Sorafenib; Drug: methotrexate, hydrocortisone and cytarabine with leucovorin

Interventions

Crenolanib 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.

Also known as: CP-868,596, IND 112201

Study Participants

Sorafenib 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.

Also known as: Sorafenib tosylate, BAY-43-9006, Nexavar®

Study Participants

methotrexate, hydrocortisone and cytarabine with leucovorin 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.

Also known as: Triple IT chemotherapy

Study Participants

Eligibility Criteria

• Age: 1 Year - 39 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Arog Pharmaceuticals, Inc.: collaborator
• Ohio State University: collaborator

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

crenolanib; Sorafenib; Methotrexate; Hydrocortisone; Cytarabine; Leucovorin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Coenzymes; Enzymes and Coenzymes

Study Officials

• Hiroto Inaba, MD, PhD

  St. Jude Children's Research Hospital

  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

Study Record Dates

• First Submitted: October 17, 2014
• First Posted: October 21, 2014
• Study Start: April 2, 2015
• Primary Completion: October 17, 2016
• Study Completion: October 17, 2016
• Last Updated: October 3, 2017

Record last verified: 2017-10

Locations

US (1)