A Study to Find the Highest Dose of Imetelstat in Combination With Fludarabine and Cytarabine for Patients With AML, MDS or JMML That Has Come Back or Does Not Respond to Therapy
This phase I trial tests the safety, side effects, and best dose of imetelstat in combination with fludarabine and cytarabine in treating patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML) that has not responded to previous treatment (refractory) or that has come back after a period of improvement (recurrent). Imetelstat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as fludarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving imetelstat in combination with fludarabine and cytarabine may work better in treating patients with refractory or recurrent AML, MDS, and JMML.
Eligibility criteria
This trial does not accept healthy volunteers
Qualifiers
Patients must be ≥ 1 year and ≤ 18 years of age at the time of study enrollment
Second or greater relapse or refractory AML, including isolated extramedullary disease (EMD), but excluding isolated central nervous system (CNS) or isolated testicular relapse
First or greater relapse of MDS
First or greater relapse of JMML
Disqualifiers
Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, or because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (eg, male or female condom) for the duration of the study. Abstinence is an acceptable method of birth control. Women of childbearing potential must use highly effective contraception in addition to a barrier method during treatment and for at least 1 month after the last dose of imetelstat or longer if required by the institutional guidelines for conventional chemotherapy (fludarabine/cytarabine). Male patients who can father a child should use contraception during treatment and for 3 months after the last dose of imetelstat or longer if required by the institutional guidelines for conventional chemotherapy (fludarabine/cytarabine). Imetelstat should not be administered to nursing mothers
Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. Patients may be on physiological doses of steroids (equivalent to ≤ 10 mg prednisone daily for patients ≥ 18 years or ≤ 10mg/m²/day [up to a maximum of 10 mg/day] for patients < 18 years). If used to modify immune adverse events related to prior therapy, ≥ 14 days must have elapsed since last dose of corticosteroid
Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy
Trial design
Design model
Sequential
Treatments tested in this trial
Biospecimen Collection
Procedure/Surgery
Undergo blood and CSF sample collection
Bone Marrow Aspiration
Procedure/Surgery
Undergo bone marrow biopsy and aspiration
Bone Marrow Biopsy
Procedure/Surgery
Undergo bone marrow biopsy and aspiration
Cytarabine
Drug
Given IV and IT
Echocardiography Test
Procedure/Surgery
Undergo ECHO
Fludarabine
Drug
Given IV
Hydrocortisone Sodium Succinate
Drug
Given IT
Imetelstat
Biological/Vaccine
Given IV
Leucovorin Calcium
Drug
Given IV or PO
Lumbar Puncture
Procedure/Surgery
Undergo lumbar puncture
Methotrexate
Drug
Given IT
Treatment groups
36 Participants
are divided into 1 treatment group
Group A: Treatment (Imetelstat, fludarabine, cytarabine)Experimental treatment 11 interventions
Trial outcomes
Primary outcomes
1
Dose limiting toxicities of imetelstat administered in combination with fludarabine and cytarabine
Frequency percent (%) of patients with acute myeloid leukemia (AML) in second or greater relapse or refractory to relapse therapy who experience a cycle 1 dose limiting toxicity to imetelstat administered in combination with fludarabine and cytarabine stratified by dose level.
Time frame
During cycle 1 of therapy (each cycle is 28 days)
Secondary outcomes
1
Incidence of adverse events of imetelstat administered in combination with fludarabine and cytarabine
Frequency (%) of patients with acute myeloid leukemia in second or greater relapse or refractory to relapse therapy who experience adverse events at least possibly attributable to imetelstat administered in combination with fludarabine and cytarabine stratified by dose level graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Time frame
Up to 2 years from study entry
2
Area under the drug concentration curve of imetelstat administered in combination with fludarabine and cytarabine
Median (minimum \[min\], maximum \[max\]) of the area under the drug concentration curve of imetelstat administered in combination with fludarabine and cytarabine assessed during cycle 1 at 0, 0.5, 1, 4-5, 6-8 and 24-hours post administration.
Time frame
Up to 24 hours
3
Maximum serum concentration of imetelstat administered in combination with fludarabine and cytarabine
Median (min, max) of the maximum serum concentration of imetelstat administered in combination with fludarabine and cytarabine assessed during cycle 1 at 0, 0.5, 1, 4-5, 6-8 and 24-hours post administration.
Time frame
Up to 24 hours
4
Clearance of imetelstat administered in combination with fludarabine and cytarabine
Median (min, max) of the clearance of imetelstat administered in combination with fludarabine and cytarabine assessed during cycle 1 at 0, 0.5, 1, 4-5, 6-8 and 24-hours post administration.
Time frame
Up to 24 hours
Other outcomes
1
Pharmacodynamics
Will characterize the pharmacodynamic properties of imetelstat in pediatric patients with refractory or second or greater relapse of AML, or first or greater relapse of myelodysplastic syndrome, or juvenile myelomonocytic leukemia.
Time frame
Up to 2 years
2
Telomerase activity
Will be assessed in peripheral blood mononuclear cells.
Time frame
Cycle 1 day 1, pre-dose and cycle 1 day 2 at 24 hours (each cycle is 28 days)
3
Cytogenetic abnormalities
Compare baseline cytogenetic abnormalities vs. change of cytogenetic abnormalities after treatment.
Time frame
At baseline and after cycle 2 (each cycle is 28 days)
4
Mutational status
Compare baseline mutational status vs. change of mutational status after treatment.
Time frame
After cycle 1 and 2
Sponsors and contacts
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