CompletedPhase 2ACTRN12611000814976

A Multicentre trial for the treatment of adolescents aged 15 years and above, and young adults aged up to 40 years, with newly diagnosed Acute Lymphoblastic Leukaemia (ALL)

A phase II trial of an intensive pediatric protocol incorporating post-induction stratification based on minimal residual disease levels for the treatment of adolescents aged 15 years and above, and young adults aged up to 40 years, with newly diagnosed ALL

Sponsor

Australasian Leukaemia and Lymphoma Group

Enrollment

100 participants

Start Date

Sep 21, 2012

Study Type

Interventional

Conditions

Untreated ALL aged 15 to 40 years

Summary

This study will be a national clinical trial that will evaluate the safety and efficacy of a chemotherapy treatment, administered to adolescents and young adults with a newly diagnosed bone marrow cancer, called acute lymphoblastic leukaemia (ALL). Who is it for? You may be able to join this study if you are aged between 15 to 40 years and have been recently diagnosed with acute lymphoblastic leukaemia (ALL), for which you have not yet undergone any treatment. Trial details: ALL is the most common form of childhood cancer, but in over 80% of children it can be cured with chemotherapy. Adults with ALL do much worse and this trial will examine whether exactly the same treatment given to children can also be given to adults, and if so, are the results as good. In order to determine this, all patients in this trial will be administered the same chemotherapy treatment given to children. Patients' response to this chemotherapy will determine subsequent treatment. Participants in this trial will be regularly assessed throughout this trial to determine remission rates, survival, toxicity and quality of life.

Eligibility

Sex: Both males and femalesMin Age: 15 YearssMax Age: 40 Yearss

Inclusion Criteria11

All of the following criteria must be satisfied for registration on the study.
A morphological diagnosis of ALL byWHO criteria, confirmed by immunophenotyping and cytogenetics. All clinico-pathological subtypes will be eligible, except for mature B or Burkitt ALL (L3).
Has provided written, informed consent
Available for follow up for at least 3 years
Males capable of parenting a child and women of childbearing potential must be using a medically acceptable and adequate method of contraception while undergoing protocol treatment and for 28 days following the last dose of protocol treatment. Note: due to a potentially increased risk of thrombosis in asparaginase containing regimens, cessation of the combined oral contraceptive in female patients should be considered and an alternative medically appropriate form of contraception be instituted.
Bone marrow blast count >/= 20%
Adequate renal and hepatic function at Screening as defined by:
a. Total bilirubin <2.5 x ULN unless medically correctable
b. Serum creatinine less than or equal to 200 micromol/L unless medically correctable
Normal left ventricular ejection fraction, according to institutional criteria. If the clinical circumstances require that treatment must be given urgently before this can be ascertained, the absence of clinical cardiac impairment is acceptable, provided that a normal left ventricular ejection fraction is confirmed prior to the first consolidation cycle.
An ECOG performance status score of 0-3 at Screening

Exclusion Criteria11

Presence of any of the following criteria will exclude the subject from registration on the study.
Subjects aged less than 15 or more than 40 years at Screening
Patients known to have Philadelphia chromosome-positive disease
Presence of serious cardiac, pulmonary, hepatic or renal disease.
Previous treatment for ALL or history of cancer (other than basal cell skin cancer or carcinoma of the cervix in situ, or other localised cancer treated by surgical excision only more than 5 years earlier without evidence of recurrence in the intervening period).
Contraindication to the use of the study drugs.
Positive for HIV, or evidence of uncontrolled Hepatitis B or C infection
Severe active infection
Has any other clinically important abnormalities as determined by the investigator that may interfere with his or her participation in or compliance with the study
Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent and registration in the trial.
Pregnancy-Women who are pregnant at the time of diagnosis will not be excluded from the trial per se. The specific circumstances will require discussion between the patient, the hematologist responsible for her care, and the attending obstetrician. The management plan should then be discussed with one of the study

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Interventions

All patients will commence treatment with Protocol I which is an intensive chemotherapy induction protocol. Various prognostic factors such as cytogenetic abnormalities, initial response to prednisolone, achievement of remission, and MRD levels after induction and consolidation, will determine whether patients continue treatment outlined in Protocol M, or are to be treated on the High Risk protocol, or undergo allogeneic Haemopoietic Cell Transplantation (HCT). Patients removed for allogeneic HCT will be withdrawn from the study, but will continue to be followed, with relapse, disease-free and overall survival data being recorded. PROTOCOL I, Phase 1, Days 1-35: i) Intrathecal Methotrexate (IT MTX) on days 1, 15, 33. ii) Prednisolone (PRED) 60mg/m^2/day orally in 2 divided doses per day on Days 1-7. On Days 8-28 PRED 60mg/m^2/day in 3 divided doses. On Days 29-38: PRED taper in 3 stages every 3 days. Reduce dosage by half at each stage. iii) Vincristine (VCR) 1.5mh/m^2/day IV bolus (maximum single dose 2mg) Days 8, 16, 22 and 29. iv) Daunorubicin (DNR) 30mg/m^2 IV over 1 hr Days 8, 16, 22, 29. v) Pegylated Asparaginase (LINK) 1000U/m^2 IM or IV on Days 8 and 22. PROTOCOL I, Phase 2, Days 36-64: i) Cytarabine (ARA-C) 75mg/m^2/day IV or SC in 4 x 4 day blocks on Days 36, 37, 38, 39; Days 43, 44, 45, 46; Days 50, 51, 52, 53; Days 57, 58, 59, 60. ii) Cyclophosphamide (CPA) 1000mg/m^2/day/IV over 1 hour, Days 36 and 64. iii) 6-Mercaptopurine (MP) 60mg/m^2/day orally on Days 36-63, 28 days total. iv) Intrathecal Methotrexate (IT MTX) on Days 43 and 57 with the second and fourth cytarabine blocks. PROTOCOL M for Standard and Medium Risk only. Scheduled to commence on Day 79 after the start of Protocol 1, provided there is adequate count recovery. i) 6-Mercaptopurine (MP) 25 mg/m^2/day orally over 8 weeks, Days 1-56. ii) High Dose Methotrexate (HD-MTX) 5g/m^2 as a continuous infusion over 24 hours, on Days 8, 22, 36, 50. iii) Intrathecal Methotrexate (IT MTX) administered at 2 hours after the start of the MTX-infusion on Days 8, 22, 36, 50. HIGH RISK PROTOCOL, Block HR-1, normally begins directly after completion of Protocol I. i) Dexamethasone (DEXA) 20mg/m^2/d orally or by IV in 2 divided doses on Days 1-5. ii) Vincristine (VCR) 1.5mg/m^2/daily (maximum single dose 2mg) IV on Days 1 and 6. iii) High Dose Methotrexate (HD-MTX) 5g/m^2, infused IV over 24 hours on Day 1. iv) Cyclophosphamide (CPA) 200mg/m^2/twice daily IV over 1 hour, Days 2-4. v) Cytarabine (HD-ARA-C) 2g/m^2/twice daily, IV over 3 hours on Day 5. vi) Pegylated Asparaginase (ASP) 1000U/m^2 IM or IV on Day 6. vii) Intrathecal Methotrexate (MTX) 12 mg/Cytarabine (ARA-C) 30mg/Hydrocortisone 50mg on Day 1. HIGH RISK PROTOCOL, Block HR-2: The doses and scheduling of i) DEXA ii) HD-MTX/LCV-Rescue iii) ASP iv) MTX/ARA-C/HYDROCORTISONE IT are the same as in block HR-1. Additional therapy in HR2: v) Vindesine (VDS) 3mg/m^2/daily (maximum single dose 5mg) IV on Days 1 and 6. vi) Ifosfamide (IFO) 800mg/m^2/twice daily IV over 1 hour on Days 2-4. vii) Daunorubicin (DNR) 30mg/m^2/daily IV over 1 hour on Day 5. HIGH RISK PROTOCOL, Block HR-3: i) DEXA ii) ASP as in block HR-1. Additional therapy in HR-3: iii) Cytarabine (HD-ARA-C) 2g/m^2/twice daily IV over 3 hours, Days 1-2. iv) Etoposide (VP-16) 100mg/m^2/twice daily IV over 1 hour every 12 hours, Days 3-5. v) Intrathecal Methotrexate, Cytarabine, Hydrocortisone (MTX/ARA-C/HYDROCORTISONE IT) on Day 5. PROTOCOL II, Phase 1, Days 1-35: i) Dexamethasone (DEXA) 10mg/m^2/day orally in 2-3 divided doses, Days 1-21. From Day 22 on, reduce the dose every 3 days by half and stop on Day 29. ii) Vincristine (VCR) 1.5mg/m^2/day IV bolus (maximum single dose 2mg) on Days 8, 15, 22, 29. iii) Doxorubicin (DOX): 30mg/m^2/day IV over 1 hour on Days 8, 15, 22, 29. iv) Pegylated L’Asparaginase 1000U/m^2 IM or IV on Day1. v) Intrathecal Methotrexate (IT MTX) on Days 1, 18 ONLY IF CNS disease at diagnosis. PROTOCOL II, Phase 2, Days 36-50: i) Cytarabine (ARA-C) 75mg/m^2/day IV or SC in 2 x 4 day blocks. Days 36, 37, 38, 39 and Days 43, 44, 45, 46. ii) Cyclophosphamide (CPA) 1000mg/m^2 IV over 1 hour, Day 36. iii) 6-Thioguanine (6-TG) 60mg/m^2/day orally, Day 36-49, a total of 14 days. iv) Intrathecal Methotrexate (IT MTX) at the same time as the first dose of Cytarabine in Block 1 (Day 36) and Block 2 (Day 43). MAINTENANCE THERAPY begins 2 weeks after the end of Protocol II. Total therapy, calculated from the start of Protocol I, is 24 months for all patients. i) 6-Mercapoturine (MP) 50mg/m^2/day orally. ii) Methotrexate (MTX) 20mg/m^2/week, orally once a week at night.