Acute Myeloid LeukemiaPhase 1NCT02270788
Crenolanib in Combination With Sorafenib in Patients With Refractory or Relapsed Hematologic Malignancies
A Phase 1 study testing Crenolanib, Sorafenib and methotrexate, hydrocortisone and cytarabine with leucovorin in people with Acute Myeloid Leukemia, run by St. Jude Children's Research Hospital at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 1 year to 39 years
- Conditions the study is for
- Acute Myeloid Leukemia
- What is being tested?
- Crenolanib, Sorafenib and methotrexate, hydrocortisone and cytarabine with leucovorin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- 2 Apr 2015to 17 Oct 2016
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 39 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
St. Jude Children's Research Hospital
Memphis, Tennessee, 38105
About this study
Official title: A Phase I Pharmacokinetic, Pharmacodynamic and Feasibility Study of Crenolanib in Combination With Sorafenib in Patients With Refractory or Relapsed Hematologic Malignancies (ARO-008)
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.
Read more
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.
Read the 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
- Being tested
- Crenolanib, Sorafenib, methotrexate, hydrocortisone and cytarabine with leucovorin
- Medical subject headings
- Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CrenolanibDrug
Also called CP-868,596, IND 112201
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.
SorafenibDrug
Also called Sorafenib tosylate, BAY-43-9006, Nexavar®
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 leucovorinDrug
Also called Triple IT chemotherapy
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.
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: Drug: Crenolanib; Drug: Sorafenib; Drug: methotrexate, hydrocortisone and cytarabine with leucovorin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Through Day 28 of Course 1
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Oct 2014 (estimated)
- Study start2 Apr 2015
- Primary completion17 Oct 2016
- Study completion17 Oct 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Myeloid LeukemiaStudies of the same condition, open and under way.
- More trials run by St. Jude Children's Research HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- St. Jude Children's Research Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Arog Pharmaceuticals, Inc., Ohio State University
- Responsible party
- Sponsor
- Investigators
- Hiroto Inaba, MD, PhD, Principal investigator, St. Jude Children's Research Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02270788
- Sponsor's protocol ID
- RELHEM2
- Other IDs
- NCI-2014-01784
- Status last verified
- Oct 2017
- First submitted
- 17 Oct 2014
- Last updated
- 3 Oct 2017
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Oct 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Pharmacokinetic, Pharmacodynamic and Feasibility Study of Crenolanib in Combination With Sorafenib in Patients With Refractory or Relapsed Hematologic Malignancies (ARO-008)
- ClinicalTrials.gov ID
- NCT02270788
- Acronym / sponsor ID
- RELHEM2
- Conditions
- Acute Myeloid Leukemia
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- St. Jude Children's Research HospitalUniversity, hospital or other
- Collaborators
- Arog Pharmaceuticals, Inc., Ohio State University
- Study start
- 2 Apr 2015 (actual)
- Primary completion
- 17 Oct 2016 (actual)
- Study completion
- 17 Oct 2016 (actual)
- First posted
- 21 Oct 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Study Participants | Experimental | Drug: Crenolanib, Drug: Sorafenib, Drug: methotrexate, hydrocortisone and cytarabine with leucovorinAll participants who consent and are enrolled on the study. Interventions: Crenolanib, sorafenib, triple intrathecal chemotherapy (methotrexate, hydrocortisone and cytarabine with leucovorin). |
Who may qualify
- Ages
- 1 year to 39 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (22 listed)
- Participant has a relapsed or refractory hematologic malignancy (with any measurable disease) with FLT3-ITD or TKD mutations and one of the following diagnoses:
- 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.
Key exclusion criteria (8 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CrenolanibAlso: CP-868,596, IND 112201Day 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. | Drug | Study Participants |
| SorafenibAlso: Sorafenib tosylate, BAY-43-9006, Nexavar®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. | Drug | Study Participants |
| methotrexate, hydrocortisone and cytarabine with leucovorinAlso: Triple IT chemotherapyTriple 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. | Drug | Study Participants |
Primary outcome
Dose-limiting toxicity (DLT)
Time frame: Through Day 28 of Course 1
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.
Maximum tolerated dose (MTD)
Time frame: Through Day 28 of Course 1
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.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Oct 2017.
- St. Jude Children's Research HospitalLink provided by the sponsor.
- Clinical Trials Open at St. JudeLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hiroto Inaba, MD, PhD principal investigator
St. Jude Children's Research Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Crenolanib, Sorafenib and methotrexate, hydrocortisone and cytarabine with leucovorin in people with Acute Myeloid Leukemia, run by St. Jude Children's Research Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Dose-limiting toxicity (DLT) (time frame: Through Day 28 of Course 1). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Oct 2017.