RecruitingPhase 2ACTRN12622001232729

A multi-centre phase II, Australian and New Zealand, exploratory study of amendments to conditioning regimens in haplo-identical stem cell transplantation

Sponsor

St Vincent's Hospital, Sydney

Enrollment

127 participants

Start Date

Sep 5, 2023

Study Type

Interventional

Conditions

transformed AML/ MDS Myeloproliferative Disorders Hodgkin's Disease Acute Lymphoblastic Leukaemia Acute Myeloid Leukaemia Chronic Myeloid Leukaemia Non Hodgkin's Disease

Summary

People who have been diagnosed with a blood cancer that has a risk of relapse, (e.g. Acute Myeloid Leukemia, Myeloid Dysplastic Syndrome, Chronic Myeloid Leukemia, Acute Lymphoblastic Leukemia, Hodgkin's Lymphoma or Non-Hodgkin's Lymphoma) may benefit from having a transplant of healthy stem cells into their bone marrow to encourage their body to produce healthy cells. This treatment has a high risk of transplant rejection and so patients often need to take immuno-suppressing drugs for a time before and after the transplant to ensure the transplant is not rejected. This study aims to assess 4 different immuno-suppressing treatment regimes (drugs and body irradiation/radiotherapy) to determine which treatment is best at suppressing the rejection response without compromising the overall health of the patient. Who is it for? You may be eligible for this study if you are aged 16 to 75 years of age, you have been diagnosed with a blood cancer that has a risk of relapse and your doctor has recommended that a stem cell transplant is indicated. You may also need to meet additional criteria (heart, lung and kidney health criteria) in order to be eligible for this study. Study details Participants in this study will take part in one of two separate sub-studies. The decision of which of the two sub-studies a participant will take part in is at the discretion of the study investigator. The two sub-studies are: 1. Reduced Intensity Conditioning (RIC) -Sub-study 1: contains two sequential treatment arms. The first treatment arms.will examine using will use standard of care radiation but at a higher dose with fludarabine. The second treatment arm will use of treosulfan instead of standard of care busulfan with fludarabine. Patients will have scans and blood tests before and after the transplant. Medical review will occur daily whilst in hospital and then once discharged as medically required ( may start weekly then monthly) 2 Myeloablative Conditioning (MAC) - Sub-study 2: contains 2 treatment arms running concurrently. One will use of treosulfan instead of standard of care busulfan with fludarabine and the other will use standard of care radiation but at a higher dose. Patients will have scans and blood tests before and after the transplant. Medical review will occur daily whilst in hospital and then once discharged as medically required ( may start weekly then monthly) It is hoped this research will demonstrate that one (or many) of the treatment regimes tested is safe for cancer patients and effective at keeping the transplant rejection response rate low. The best treatment regime may then be tested in a larger randomised trial that could benefit future patients with blood cancers.

Eligibility

Sex: Both males and femalesMin Age: 16 YearssMax Age: 75 Yearss

Plain Language Summary

Simplified for easier understanding

For patients with certain blood cancers — such as leukaemia, lymphoma, or myelodysplastic syndrome — who have a high risk of relapse, a stem cell transplant from a close family member (called a haploidentical or "half-matched" transplant) can be a lifesaving option, particularly when a fully matched donor is not available or time is critical. To prevent the body from rejecting the transplanted cells, patients receive intensive conditioning treatments — combinations of chemotherapy and sometimes radiation — before the transplant. This study is testing four different conditioning regimens across two sub-studies (reduced intensity and full intensity) to find which combination best suppresses rejection while keeping the patient as healthy as possible. The treatments being tested include newer drug combinations and modified radiation dosing, with the aim of producing better transplant outcomes with fewer side effects. You may be eligible if you are aged 16 to 75, have a high-risk blood cancer for which a transplant is recommended, have a first-degree relative who is a half-matched donor, and have adequate heart, lung, and kidney function. You would not be eligible if you are pregnant, HIV positive, have refractory (non-responding) cancer, severe organ dysfunction, or have previously had an allogeneic (donor) stem cell transplant.

This summary was AI-generated to explain the trial in plain language. It is not medical advice. Always discuss eligibility with your doctor before enrolling in a clinical trial.

Interested in this trial?

Get notified about updates and connect with the research team.

Interventions

This is a multi-centre Phase II exploratory trial in haploidentical stem cell transplantation consisting of two distinct sub studies (Reduced Intensity Conditioning (RIC) and Myeloablative Conditioning (MAC). Patients at the discretion of their treating stem cell transplant specialist will be assigned to either RIC or MAC sub-study on the completion of assessments to determining their level of physical well-being. Regardless which arm you are enrolled in, patients will have central venous access performed upon admission to hospital as per institutional guidelines. Intravenous fluids and supportive care with anti-microbials, ganciclovir, anti-emetics, allopurinol, trimethoprim/co-trimoxazole will be administered according to local allogeneic stem cell transplant protocols. Once they are admitted into hospital for the transplant, patients will receive medication to treat any side effects they are experiencing and nutritional support as well as prophylaxis anti- viral/ bacteria according to the patients local institutional guidelines. In addition, Day 0 is the day the patient will receive the donor stem cells known as day of transplant. If a patient's stem cell transplant specialist has selected to use MYELOABLATIVE CONDITIONING REGIMENS (MAC) they will be enrolled into Fludarabine/Treosulfan protocol (cohort 1) or Fludarabine/TBI 1200cGy protocol (cohort 2). A patient enrolled into the Fludarabine/Treosulfan protocol (cohort 1) will be given the following regimen. • Fludarabine will be administered intravenously once a day at a dose of 30mg/m2 over 60 minutes on days -6, -5, -4, -3, -2. • Treosulfan will be administered intravenously as a two hour infusion at a dose of 14g/m2 on days -4 to day-2 prior to fludarabine • Cyclophosphamide will be given intravenously as post -transplant Graft Versus Host Disease (GVHD) prophylaxis on Day +3 and Day +4 at a dose of 50mg/kg. Mesna will be administered as per institutional guidelines. The cyclophosphamide will be given as a one hour infusion with pre and post intravenous fluids as per institutional guidelines. • Cyclosporine 1.5mg/kg will be given twice a day as an intravenous infusion over 2 hours from Day +5 onwards until the donor stem cells have started to function and the patient is able to tolerate oral cyclosporine. The dose of oral cyclosporine will be re-assessed at Day +60 and weaned if possible to cease at D90 - D120 provided no Acute GVHD grade II-IV occurs. • Mycophenolate will be given orally or IV at a dose of 15mg/kg three times a day (rounded to the nearest 250mg) from Day +5 to Day +35. If patients are enrolled instead into the Fludarabine/TBI 1200cGy protocol (cohort 2), they will receive the following regimen: • Fludarabine will be administered intravenously daily at a dose of 30mg/m2 over 60 minutes on Days -7, D-6 and D-5. • Total Body irradiation (TBI) will be administered daily at a dose of 150cGy from D-4 to D-1 (total dose 1200cGy). • Cyclophosphamide will be given intravenously daily as post -transplant GVHD prophylaxis on D+3 and D+4 at a dose of 50mg/kg. Mesna will be administered as per institutional guidelines. The cyclophosphamide will be given as a one hour infusion with pre and post intravenous fluids as per institutional guidelines. • Cyclosporine 1.5mg/kg will be given twice a day as an intravenous infusion over 2 hours from Day +5 onwards until the patients has engrafted and is able to tolerate oral cyclosporine. The dose of oral cyclosporine will be re-assessed at Day +60 and weaned, if possible, to cease between D+90-D+120 provided no Acute GVHD grade II-IV occurs. • Mycophenolate will be given orally or IV at a dose of 15mg/kg three times a day (rounded to the nearest 250mg) from Day+5 to Day+35 Patients who are assessed as not suitable for MAC regimen will be offered/ enrolled into The Reduced intensity conditioning (RIC) sub-study. The Reduced intensity conditioning (RIC) sub-study contains two sequential cohorts. The first cohort will use radiation therapy called total body irradiation with Fludarabine. Once 25 patients have being enrolled in the first treatment arm, enrolled in the second treatment arm will commence. The second treatment arm will use Fludarabine with treosulfan and post transplant cyclophosphamide as Graft Versus Host Disease (GVHD) prophylaxis Once 25 patients have being enrolled in the first treatment arm, enrolled in the second treatment arm will commence. The second treatment arm will Treatment Arm # 1: Fludarabine/TBI 400cGy. A maximum of 52 patients will be accrued in the first treatment arm and • Fludarabine will be given intravenously daily at 30 mg/m2 on days -6, -5, -4, -3, and -2 (total dose 150 mg/m2) • Cyclophosphamide will be administered daily at a dose of 14.5 mg/kg intravenously on days -6 and -5 • Total body irradiation will be given 200 cGy fraction daily for two doses on Day -2 and Day-1 • Cyclophosphamide will be administered daily at a dose of 50 mg/kg intravenously as post-transplant GHVD prophylaxis on days +3 and +4. Mesna will also be administered as per institutional guidelines. The cyclophosphamide will be given as a one hour infusion with pre and post intravenous fluids as per institutional guidelines. • Tacrolimus in 2 divided oral doses per day until the drug level reaches a target of 5-15 ng/ml will be started on day +5. This will be assessed by blood test taken daily. The dose of oral tacrolimus will be re-assessed at Day +60 and weaned, if possible, to cease at D90-D120 provided no Acute Graft Versus Host Disease grade II-IV occurs. • Mycophenolate mofetil taken orally three times a day at 15 mg/kg will be start on day +5 and cease on D35.. Once RIC treatment arm #1 has reached it maximum numbers and participants enrolled have tolerated the treatment, a maximum of 25 patients will be enrolment into Treatment Arm # 2 using Fludarabine/Treosulfan. Patients in this treatment arm will receive: • Fludarabine will be given intravenously daily at 30 mg/m2 on days -6, -5, -4, -3, and -2 (total dose 150 mg/m2) • Treosulfan will be given intravenously daily at 10mg/m2 as a 2 hour infusion on days -4, -3,-2, and D-1 prior to fludarabine • Cyclophosphamide will be administered daily at a dose of 50 mg/kg intravenously as post-transplant GHVD prophylaxis on days +3 and +4. Mesna will also be administered as per institutional guidelines. The cyclophosphamide will be given as a one hour infusion with pre and post intravenous fluids as per institutional guidelines. • Tacrolimus in 2 divided oral doses per day until the drug level reaches a target of 5-15 ng/ml will be started on day +5. This will be assessed by blood test taken daily. The dose of oral tacrolimus will be re-assessed at Day +60 and weaned, if possible, to cease at D90-D120 provided no Acute Graft Versus Host Disease grade II-IV occurs. • Mycophenolate mofetil taken orally three times a day at 15 mg/kg will be starton day +5 and cease on D35. Regardless which arm a patient is enrolled into, they are admitted into hospital for the transplant, patients will receive medication to treat any side effects they are experiencing and nutritional support as well as prophylaxis anti- viral/ bacteria according to the patients local institutional guidelines. Weekly monitoring of CMV and EBV infection will take place from Day+21 until Day +90. All patients will have weekly clinical assessment done by the treating physician or team following discharge along with routine blood tests up to day +100. Subsequently, formal follow-up for trial assessments will occur on Day +180 then yearly from year 1-5 post HSCT. Formal disease assessment will be made at Day +28-42 (post BMAT), Day +100, Day +180, then yearly from Year 1-5. using local institutional guidelines.