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Clofarabine Pre-allogeneic Stem Cell Transplant for Non-remission AML
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Acute Myeloid Leukemia | Drug: Clofarabine Drug: Fludarabine Drug: Busulfan Procedure: Total Body Irradiation (TBI) Drug: Cyclophosphamide Drug: Granulocyte Colony-Stimulating Factor Drug: Tacrolimus Drug: Cellcept | Phase 2 |
Approximately 30-40% of patients with acute myeloid leukemia (AML) experience induction failures. In these patients who do not achieve remission with two cycles of standard induction therapies, the probability of achieving remission with subsequent inductions is limited. Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but high relapse rate and transplant-related mortality often preclude them to proceed to transplant. Thus, AML not in remission at time of HSCT remains a huge unmet need in current HSCT practice, particularly if the patient does not have a Human Leukocyte Antigen (HLA)-matched donor identified by the time of two induction failures.
Salvage chemotherapy with clofarabine appears to be another promising option in relapsed and refractory AML. Clofarabine is a second-generation purine nucleoside analog with substantial single-agent activity in adult patients with AML. It is an effective immunosuppressive agent and several trials have shown the feasibility of conditioning with clofarabine-based regimen.
In the past, a conditioning regimen of clofarabine with busulfan (4 doses) has been successfully used prior to allogeneic stem cell transplantation for non-remission AML with day +30 complete remission rates were 90-100%. However, these patients were transplanted with HLA matched donors. This study will examine those patients undergoing haploidentical transplantation.
Achieving a long-term remission is clearly the goal of AML treatment. For this clinical trial, the Investigators propose to examine the use of clofarabine pre- haploidentical (related) stem cell transplantation for patients who have experienced two induction failures. Even in previous Clofarabine/Busulfan4 studies, the Investigators observed a relapse rate of about 45% after achieving the first complete remission. With further development of molecularly targeted maintenance therapies, reliable protocols to bring these patients into the early complete remission will be essential.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 20 participants |
| Allocation: | N/A |
| Intervention Model: | Sequential Assignment |
| Intervention Model Description: | Dose de-escalation: Enrollment will begin at 30 mg/m2 to analyze any grade 4-5 organ toxicities as defined in Section 12.2. If the trial is stopped due to excessive toxicities, then dose de-escalation to 20 mg/m2 will occur for the next cohort of participants. For each participant, the observation period is from start of treatment through post-transplant day +30. Adverse effects will be continuously monitored as patients are enrolled. The trial will be stopped when the toxicity rate exceeds 20% with a posterior probability of 80% and a margin of no more than 5%. This leads to the following stopping rule: the trial will be stopped if 2 of the first 3 subjects experience grade 4-5 organ toxicity, or 3 out of 6, 4 out 9, 5 out of 12, 6 out of 16, or 7 out 19. |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Clofarabine Followed by Hematopoietic Stem Cell Transplant Using Fludarabine, Busulfan, and Total-Body Irradiation With Post-Transplant Cyclophosphamide for Non-remission Acute Myeloid Leukemia |
| Actual Study Start Date : | June 3, 2020 |
| Estimated Primary Completion Date : | September 3, 2021 |
| Estimated Study Completion Date : | July 3, 2026 |
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Clofarabine 30 mg/m^2
Clofarabine 30 mg/m^2 IV once a day for 5 days prior to the initiation of the standard conditioning regimen for the stem cell transplant infusion (Day 0). In the event of excessive toxicities related to the clofarabine, a dose de-escalation to 20 mg/m^2 will occur for the next cohort of subjects. Day -14 through Day -10 Clofarabine 30 mg/m^2, Day - 9 Day of rest (no scheduled conditioning medications), Day - 8 Day of rest, Day - 7 Day of rest, Day - 6 Fludarabine 40 mg/m^2 IV and Busulfan 3.2 mg/kg IV, Day - 5 Fludarabine 40 mg/m^2 IV and Busulfan 3.2 mg/kg IV, Day - 4 Fludarabine 40 mg/m^2 IV, Day - 3 Fludarabine 40 mg/m^2 IV, Day - 2 Day of Rest, Day -1 Total Body Irradiation 200 cGys, Day 0 stem cell transplant infusion, Day +3 Cyclophosphamide 50 mg/kg IV, Day +4 Cyclophosphamide 50 mg/kg IV, Day +5 Start G-CSF, Tacrolimus, and MMF |
Drug: Clofarabine
Clofarabine to be administered pre-stem cell transplant infusion ("Day 0") once a day for 5 days total.
Other Name: Clolar
Drug: Fludarabine Fludarabine will be administered once a day for 4 days as part of the transplant conditioning regimen.
Other Name: Fludara
Drug: Busulfan Busulfan will be administered once a day for 2 days as part of the transplant conditioning regimen.
Other Name: Busulfex
Procedure: Total Body Irradiation (TBI) TBI will be administered at a dose of 200cGys on Day -1 prior to transplant
Other Name: TBI
Drug: Cyclophosphamide Cyclophosphamide will be given once a day for 2 days after the transplant infusion.
Other Name: Cytoxan
Drug: Granulocyte Colony-Stimulating Factor G-CSF will be administered to subjects starting on Day +5 and will continue as clinically indicated
Other Name: Filgrastim G-CSF
Drug: Tacrolimus Tacrolimus will be administered to subjects starting on Day +5 and will continue as clinically indicated
Other Name: Prograf
Drug: Cellcept Mycophenolate Mofetil will be administered to subjects starting on Day +5 and will continue as clinically indicated
Other Name: Mycophenolate Mofetil (MMF)
|
- Incidence of complete remission (CR) [ Time Frame: 30 days ]Determine the incidence of CR at 30 days (Day +30) post stem cell transplant infusion
- Non-relapse related mortality [ Time Frame: 100 days ]Determine the rate of non-relapse related mortality at 100 days post transplant (Day +100)
- Neutrophil engraftment [ Time Frame: 1 year ]Rates of engraftment, defined as the first day of Absolute Neutrophil Count (ANC) greater than 500 for the first of three consecutive days
- Incidence of Acute graft-versus-host disease (GVHD) [ Time Frame: 100 days ]The incidence of any grade (1-4) of acute GvHD as measured from day of transplantation to Day +100 using the Glucksberg criteria.
- Severity of Acute graft-versus-host disease (GVHD) [ Time Frame: 100 days ]The highest grade (1-4) of acute GvHD experienced by participants as measured from day of transplantation to Day +100 using the Glucksberg criteria
- Incidence of Chronic GVHD [ Time Frame: 1 year ]The incidence of any grade (1-4) of acute GvHD as measured from Day +100 to Year 1 post-transplantation using the Glucksberg criteria.
- Severity of Chronic GVHD [ Time Frame: 1 year ]The highest overall grade (1-4) of chronic GvHD experienced by participants as measured from Day +100 to Year 1 post-transplantation using the Glucksberg criteria
| Ages Eligible for Study: | 18 Years to 55 Years (Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Diagnostic criteria of AML, without having achieved remission after at least 2 attempts at induction chemotherapy, no attempt of induction if relapsed within 6 months of induction or no attempt of induction if relapsed after 6 months post induction therapy.
- Age 18 to 55 years of age.
- Planned or scheduled to receive an allogeneic hematopoietic stem cell transplant (HSCT) using peripheral blood (PB) or bone marrow (BM) stem cells. Cord blood donor cells are not allowed.
- Planned or scheduled to receive a standard conditioning regimen consisting of Busulfan, Fludarabine, and TBI.
- Performance status: Karnofsky ≥ 70% within 28 days of study registration
- LVEF ≥ 50% by MUGA or echocardiogram within 28 days of study registration.
- FEV1 and FVC ≥ 50% predicted, DLCO (corrected for hemoglobin) ≥ 50% of predicted within 28 days of study registration.
- Creatinine clearance 60 mL/min/1.73 m^2 within 28 days of study registration
- Serum bilirubin less than or equal to 1.5 times upper limit of normal (ULN);
- AST/ALT less than or equal to 2.5 times ULN;
- Alkaline phosphatase less than or equal to 2.5 times ULN
Exclusion Criteria:
- Known history of non-compliance with medication, scheduled clinic visits, or self-care.
- In the opinion of the investigator, no appropriate caregivers identified.
- HIV1 (Human Immunodeficiency Virus-1) or HIV2 positive
- Active infection including Hepatitis B and Hepatitis C.
- In the opinion of the physician investigator, uncontrolled medical or psychiatric disorders.
- In the opinion of the physician investigator, uncontrolled infections, defined as positive blood cultures within 72 hours of study entry or evidence of progressive infection by imaging studies such as chest CT scan within 14 days of registration.
- Active central nervous system (CNS) leukemia.
- Prior allogeneic HSCT.
- Pregnant or breastfeeding. Women of child bearing potential (WCBP) are required to have a negative serum or urine pregnancy test within 7 days of initiation of conditioning regimen.
| Contact: Seema Naik, MD | 717-531-8678 | snaik@pennstatehealth.psu.edu | |
| Contact: Clinical Research Nurse - Leukemia | 717-531-5471 |
| United States, Pennsylvania | |
| Penn State Cancer Institute | Recruiting |
| Hershey, Pennsylvania, United States, 17033 | |
| Contact: Seema Naik, MD 717-531-6585 snaik@pennstatehealth.psu.edu | |
| Principal Investigator: | Seema Naik, MD | Penn State Cancer Institute |
| Tracking Information | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| First Submitted Date ICMJE | June 24, 2019 | ||||||||
| First Posted Date ICMJE | June 28, 2019 | ||||||||
| Last Update Posted Date | November 2, 2020 | ||||||||
| Actual Study Start Date ICMJE | June 3, 2020 | ||||||||
| Estimated Primary Completion Date | September 3, 2021 (Final data collection date for primary outcome measure) | ||||||||
| Current Primary Outcome Measures ICMJE |
Incidence of complete remission (CR) [ Time Frame: 30 days ] Determine the incidence of CR at 30 days (Day +30) post stem cell transplant infusion
|
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| Original Primary Outcome Measures ICMJE | Same as current | ||||||||
| Change History | |||||||||
| Current Secondary Outcome Measures ICMJE |
|
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| Original Secondary Outcome Measures ICMJE | Same as current | ||||||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||||||
| Descriptive Information | |||||||||
| Brief Title ICMJE | Clofarabine Pre-allogeneic Stem Cell Transplant for Non-remission AML | ||||||||
| Official Title ICMJE | Clofarabine Followed by Hematopoietic Stem Cell Transplant Using Fludarabine, Busulfan, and Total-Body Irradiation With Post-Transplant Cyclophosphamide for Non-remission Acute Myeloid Leukemia | ||||||||
| Brief Summary | The Investigators would like to study the incidence of complete remission (CR) at day +30 after Clofarabine followed by haploidentical transplant. The conditioning regimen used is Fludarabine, Busulfan (2 doses) and Total Body Irradiation (TBI) with post transplant cyclophosphamide for patients with Acute Myeloid Leukemia (AML) who are not in remission prior to considering allogeneic transplant with haploidentical donors. | ||||||||
| Detailed Description |
Approximately 30-40% of patients with acute myeloid leukemia (AML) experience induction failures. In these patients who do not achieve remission with two cycles of standard induction therapies, the probability of achieving remission with subsequent inductions is limited. Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but high relapse rate and transplant-related mortality often preclude them to proceed to transplant. Thus, AML not in remission at time of HSCT remains a huge unmet need in current HSCT practice, particularly if the patient does not have a Human Leukocyte Antigen (HLA)-matched donor identified by the time of two induction failures. Salvage chemotherapy with clofarabine appears to be another promising option in relapsed and refractory AML. Clofarabine is a second-generation purine nucleoside analog with substantial single-agent activity in adult patients with AML. It is an effective immunosuppressive agent and several trials have shown the feasibility of conditioning with clofarabine-based regimen. In the past, a conditioning regimen of clofarabine with busulfan (4 doses) has been successfully used prior to allogeneic stem cell transplantation for non-remission AML with day +30 complete remission rates were 90-100%. However, these patients were transplanted with HLA matched donors. This study will examine those patients undergoing haploidentical transplantation. Achieving a long-term remission is clearly the goal of AML treatment. For this clinical trial, the Investigators propose to examine the use of clofarabine pre- haploidentical (related) stem cell transplantation for patients who have experienced two induction failures. Even in previous Clofarabine/Busulfan4 studies, the Investigators observed a relapse rate of about 45% after achieving the first complete remission. With further development of molecularly targeted maintenance therapies, reliable protocols to bring these patients into the early complete remission will be essential. |
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| Study Type ICMJE | Interventional | ||||||||
| Study Phase ICMJE | Phase 2 | ||||||||
| Study Design ICMJE | Allocation: N/A Intervention Model: Sequential Assignment Intervention Model Description: Dose de-escalation: Enrollment will begin at 30 mg/m2 to analyze any grade 4-5 organ toxicities as defined in Section 12.2. If the trial is stopped due to excessive toxicities, then dose de-escalation to 20 mg/m2 will occur for the next cohort of participants. For each participant, the observation period is from start of treatment through post-transplant day +30. Adverse effects will be continuously monitored as patients are enrolled. The trial will be stopped when the toxicity rate exceeds 20% with a posterior probability of 80% and a margin of no more than 5%. This leads to the following stopping rule: the trial will be stopped if 2 of the first 3 subjects experience grade 4-5 organ toxicity, or 3 out of 6, 4 out 9, 5 out of 12, 6 out of 16, or 7 out 19. Masking: None (Open Label)Primary Purpose: Treatment |
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| Condition ICMJE | Acute Myeloid Leukemia | ||||||||
| Intervention ICMJE |
|
||||||||
| Study Arms ICMJE | Experimental: Clofarabine 30 mg/m^2
Clofarabine 30 mg/m^2 IV once a day for 5 days prior to the initiation of the standard conditioning regimen for the stem cell transplant infusion (Day 0). In the event of excessive toxicities related to the clofarabine, a dose de-escalation to 20 mg/m^2 will occur for the next cohort of subjects. Day -14 through Day -10 Clofarabine 30 mg/m^2, Day - 9 Day of rest (no scheduled conditioning medications), Day - 8 Day of rest, Day - 7 Day of rest, Day - 6 Fludarabine 40 mg/m^2 IV and Busulfan 3.2 mg/kg IV, Day - 5 Fludarabine 40 mg/m^2 IV and Busulfan 3.2 mg/kg IV, Day - 4 Fludarabine 40 mg/m^2 IV, Day - 3 Fludarabine 40 mg/m^2 IV, Day - 2 Day of Rest, Day -1 Total Body Irradiation 200 cGys, Day 0 stem cell transplant infusion, Day +3 Cyclophosphamide 50 mg/kg IV, Day +4 Cyclophosphamide 50 mg/kg IV, Day +5 Start G-CSF, Tacrolimus, and MMF Interventions:
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| Publications * | Not Provided | ||||||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||||||
| Recruitment Status ICMJE | Recruiting | ||||||||
| Estimated Enrollment ICMJE |
20 | ||||||||
| Original Estimated Enrollment ICMJE | Same as current | ||||||||
| Estimated Study Completion Date ICMJE | July 3, 2026 | ||||||||
| Estimated Primary Completion Date | September 3, 2021 (Final data collection date for primary outcome measure) | ||||||||
| Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
|
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| Sex/Gender ICMJE |
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| Ages ICMJE | 18 Years to 55 Years (Adult) | ||||||||
| Accepts Healthy Volunteers ICMJE | No | ||||||||
| Contacts ICMJE |
|
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| Listed Location Countries ICMJE | United States | ||||||||
| Removed Location Countries | |||||||||
| Administrative Information | |||||||||
| NCT Number ICMJE | NCT04002115 | ||||||||
| Other Study ID Numbers ICMJE | 18-011 | ||||||||
| Has Data Monitoring Committee | Yes | ||||||||
| U.S. FDA-regulated Product |
|
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| IPD Sharing Statement ICMJE |
|
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| Responsible Party | Seema Naik, MD, Milton S. Hershey Medical Center | ||||||||
| Study Sponsor ICMJE | Milton S. Hershey Medical Center | ||||||||
| Collaborators ICMJE | Not Provided | ||||||||
| Investigators ICMJE |
|
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| PRS Account | Milton S. Hershey Medical Center | ||||||||
| Verification Date | October 2020 | ||||||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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