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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01614197




Registration number
NCT01614197
Ethics application status
Date submitted
18/05/2012
Date registered
7/06/2012

Titles & IDs
Public title
A Trial of Temsirolimus With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma
Scientific title
A Phase I Trial of Temsirolimus (CCI-779, Pfizer, Inc.) in Combination With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma
Secondary ID [1] 0 0
T2014-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lymphoblastic Leukemia, Acute, Childhood 0 0
Lymphoblastic Lymphoma 0 0
Peripheral T-cell Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Temsirolimus
Treatment: Drugs - Etoposide
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Methotrexate
Treatment: Drugs - Hydrocortisone
Treatment: Drugs - Cytarabine

Experimental: Dose Level 1 - This is the starting dose of temsirolimus at 7.5 mg/m\^2 given IV. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.

Experimental: Dose Level 2 - If Dose Level 1 is tolerated, the study will escalate to Dose Level 2 following the dose escalation schedule. Dose Level 2 will be administered via IV at 10 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.

Experimental: Dose Level 3 - If Dose Level 2 is tolerated, the study will escalate to Dose Level 3 following the dose escalation schedule. Dose Level 3 will be administered via IV at 15 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8.

Experimental: Dose Level 4 - If Dose Level 3 is tolerated, the study will escalate to Dose Level 4 following the dose escalation schedule. Dose Level 4 will be administered via IV at 25 mg/m\^2. First dose of temsirolimus will be administered on Day 1, followed immediately by the first dose of IV etoposide and IV cyclophosphamide. Etoposide (100mg/m\^2) and cyclophosphamide (440 mg/m\^2) are continued for the next four days (Day 1-5). A second dose of temsirolimus is given on Day 8. Temsirolimus will not be escalated beyond Dose Level 4.


Treatment: Drugs: Temsirolimus
Dose will be assigned at study entry. Give IV over 30 minutes on days 1 and 8.

Treatment: Drugs: Etoposide
100 mg/m2 IV over 1-2 hours daily x 5 on Days 1-5.

Treatment: Drugs: Cyclophosphamide
440 mg/m2 IV daily x 5 on Days 1-5 given over 30-60 minutes.

Treatment: Drugs: Methotrexate
PATIENTS WITH CNS 1 COURSES 2, 4, 6, 8: Give intrathecally to patients who were CNS1 at study entry day 1 of each course at the doses listed below.

* Age 1 - 1.99 give 8 mg of methotrexate
* Age 2 - 2.99 give10 mg of methotrexate
* Age 3 - 8.99 give 12 mg of methotrexate
* Age = 9 give 15 mg of methotrexate

PATIENTS WITH CNS 2 or 3 DISEASE

-COURSE 1: Give intrathecally to patients with CNS 2 or 3 disease at the doses defined by age below on day 6 and then weekly until the patient is CNS 1.

COURSES 2-8: Give intrathecally to patients who were CNS 3 at study entry on day 1 of each course.

* 8 mg for patients age 1-1.99
* 10 mg for patients age 2-2.99
* 12 mg for patients 3-8.99 years of age
* 15 mg for patients \>9 years of age

Treatment: Drugs: Hydrocortisone
Given with Methotrexate and Cytarabine for patients with CNS 2 or 3 disease.

COURSE 1: Give intrathecally to patients with CNS 2 or 3 disease at the doses defined by age below on day 6 and then weekly until the patient is CNS 1.

COURSES 2-8: Give intrathecally to patients who were CNS 3 at study entry on day 1 of each course.

* 8 mg for patients age 1-1.99
* 10 mg for patients age 2-2.99
* 12 mg for patients 3-8.99 years of age
* 15 mg for patients \>9 years of age

Treatment: Drugs: Cytarabine
For Patients who are CNS1 COURSE 1: Give intrathecally to patients with CNS1 disease at the dose defined by age below on day 1 of course 1 if no other IT was given within 1 week of day 1 of course 1

* Age 1 - 1.99 give 30 mg of Cytarabine
* Age 2 - 2.99 give 50mg of Cytarabine
* Age = 3 give 70 mg of Cytabine

For Patients with CNS 2 or 3 Disease COURSE 1: Give intrathecally to patients with CNS 2 or 3 disease at the doses defined by age below on day 1 if no other IT chemotherapy given within 1 week of day 1 of course 1. Then give weekly until the patient is CNS 1 or 2 (investigator discretion). No more than 5 weekly doses to be given in cycle 1.

COURSES 2-8: Give intrathecally to patients who were CNS 2or 3 at study entry on day 1 of each course.

* 16 mg for patients age 1-1.99
* 20 mg for patients age 2-2.99
* 24 mg for patients 3-8.99 years of age
* 30 mg for patients \>9 years of age
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Patients That Experienced DLT During Cycle 1 of Therapy
Timepoint [1] 0 0
Cycle 1 (a minimum of 4 weeks and a max of 8 weeks)
Secondary outcome [1] 0 0
Response Rate at the Completion of 1 Cycle of Study Treatment
Timepoint [1] 0 0
Cycle 1 (a minimum of 4 weeks and a max of 8 weeks)
Secondary outcome [2] 0 0
Minimum Residual Disease (MRD) Levels Present at End of Cycle 1 Therapy in Patients
Timepoint [2] 0 0
Cycle 1 (a minimum of 4 weeks and a max of 8 weeks)

Eligibility
Key inclusion criteria
INCLUSION CRITERIA

-Patients must be greater than or equal to 12 months and = 21 years of age at the time of study enrollment.

Patients must have one of the following:

Leukemia

* Bone marrow involvement defined as ALL = 25% blasts (M2 or M3) with or without extramedullary involvement.
* Refractory bone marrow involvement defined as MRD = 0.1% blasts done at a COG-approved MRD testing lab after most recent treatment regimen. in the bone marrow (M23) and any CNS status. OR
* Newly diagnosed patients (T or B-cell ALL) with refractory bone marrow involvement after Consolidation therapy are eligible.
* First relapse B-cell ALL patients are eligible with refractory disease.
* Second or greater relapse B-cell patients are eligible at time of relapse or with refractory disease.
* First or greater relapse T-cell ALL patients are eligible at time of relapse or with refractory disease.
* Isolated CNS 2 or 3 patients with < 0.1% MRD bone marrow involvement are not eligible.

Lymphoma

* Patient must have relapsed or refractory lymphoblastic lymphoma or peripheral T-cell lymphoma.
* Patient must have histologic verification of disease at original diagnosis.
* Patient must have evaluable or measurable disease documented by clinical or radiographic criteria or bone marrow disease present at study entry.
* Patients may have CNS 2 or 3 disease

Karnofsky greater than or equal to 50% for patients > 16 years of age and Lansky greater than or equal to 50 for patients = 16 years of age.

Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy.

Patients with leukemia or lymphoma who relapse while receiving maintenance chemotherapy will not be required to have a waiting period before enrollment onto this study.

At least 14 days must have elapsed after the completion of cytotoxic therapy, with the exception of hydroxyurea.

Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor.

Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair

Immunotherapy: At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines. or chimeric antigen receptor T cell (CART) therapy or tumor vaccines.

Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of a monoclonal antibody. (ie: Rituximab = 66 days, Epratuzumab = 69 days). Patients must have been off blinatumomab infusion for at least 4 days and all drug-related toxicity must have resolved to grade 2 or lower as outlined in the inclusion and exclusion criteria

XRT: At least 14 days after local palliative XRT (small port); At least 84 days must have elapsed if prior TBI, craniospinal XRT or if greater than or equal to 50% radiation of pelvis; At least 42 days must have elapsed if other substantial marrow radiation.

Stem Cell Infusion: No evidence of active graft vs. host disease and at least 84 days must have elapsed after transplant or stem cell infusion.

Adequate Bone Marrow Function Defined as: Blood counts are not required to be normal prior to enrollment on trial. However, platelet count must be greater than or equal to 20,000/mm3 to initiate therapy (may receive platelet transfusions). Patients should not be known to be refractory to red blood cell or platelet transfusions.

Adequate Renal Function Defined as:

* Creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m2 or
* Normal serum creatinine based on age and gender.

Adequate Liver Function Defined as:

* Total bilirubin (sum of conjugated + unconjugated) must be less than or equal to 1.5 x normal per institutional normal values for age.
* SGPT (ALT) and SGOT (AST) must be less than 3 x institutional upper limit of normal (Grade 1 or less per CTCAE 4).

--GGT must be less than 2.5 x institutional upper limit of normal (Grade 1 or less per CTCAE 4).
* Serum albumin greater than or equal to 2 g/dL.
* The hepatic requirements may be waived for patients with elevations clearly due to leukemic infiltration after consultation with the Study Chair or Vice Chair.
* Fasting or non-fasting serum triglyceride level = 300 mg/dL and serum cholesterol level = 300 mg/dL.

Adequate Cardiac Function Defined As:

* Shortening fraction of = 27% by echocardiogram, or
* Ejection fraction of = 50% by gated radionuclide study.

Adequate Pulmonary Function Defined as:

* Pulse oximetry > 94% on room air (> 90% if at high altitude)
* No evidence of dyspnea at rest and no exercise intolerance.
* Baseline chest x-ray with no evidence of active infectious disease or pneumonitis.

Reproductive Function

* Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
* Female patients with infants must agree not to breastfeed their infants while on this study.
* Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.
* Random or fasting glucose within the upper limits of normal for age. If the initial blood glucose is non-fasting and above normal limits a fasting glucose can be obtained and must be within the upper limits of normal for age.

EXCLUSION CRITERIA

* 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.
* Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible. The definition of "investigational" for use in this protocol means any drug that is not licensed by the FDA, Health Canada or the Therapeutic Goods Administration to be sold in the countries they govern. (United States, Canada and Australia)
* Anti-cancer Agents: Patients who are currently receiving or may receive while on therapy, other anti-cancer agents, radiation therapy or immunotherapy are not eligible [except leukemia patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy]. Intrathecal chemotherapy (at the discretion of the primary oncologist) may be given up to one week prior to the initiation of study therapy.
* Anti-GVHD or agents to prevent organ rejection post-transplant: Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post transplant are not eligible for this trial. At least 3 half-lives must have elapsed after the last dose of GVHD meds.
* Anticoagulants: Patients who are currently receiving therapeutic anticoagulants (including aspirin, low molecular weight heparin, and others) are not eligible. At least 3 half-lives must have elapsed after the last dose of anticoagulants.
* Angiotensin-converting enzyme (ACE) inhibitors: Patients who are currently receiving ACE inhibitors are not eligible due to the development of angioneurotic edema-type reactions in some subjects who received concurrent treatment with temsirolimus + ACE inhibitors. At least 3 half-lives must have elapsed after the last dose of ACE inhibitors.
* Calcium Channel Blockers: Patients who are currently receiving Calcium Channel Blockers are not eligible due to the development of angioneurotic edema-type reactions in some subjects who received concurrent treatment with temsirolimus + Calcium Channel Blockers. At least 3 half-lives must have elapsed after the last dose of Calcium Channel Blockers.
* Enzyme inducing Anti-convulsants: Patients who are currently receiving enzyme inducing anticonvulsants (ie phenytoin, phenobarbitol, or carbamazepine) are not eligible. Stabilizing on a non-hepatic inducing metabolizing anti-convulsant (ie: gabapentin or levetiracetam) prior to study entry is acceptable. At least 3 half-lives must have elapsed after the last dose of enzyme inducing anti-coagulants.
* Patients receiving treatment with azoles such as fluconazole or voriconazole which are potent inhibitors of temsirolimus metabolism. At least 3 half-lives must have elapsed after the last dose of azoles.
* Patient with Burkiett's leukemia and /or lymphoma are not eligible.

Infection Criteria

Patients are excluded if they have:

* Positive blood culture within 48 hours of study enrollment;
* Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability.
* A positive fungal culture within 30 days.
* Active fungal, viral, bacterial, or protozoal infection requiring IV treatment. Chronic prophylaxis therapy to prevent infections is allowed.

Patients with Down syndrome and Fanconi Anemia are excluded.

Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with protocol treatment or required observations, interfere with consent, study participation, follow up, or interpretation of study results.

Patients with known optic nerve and/or retinal involvement (because it may not be possible to safely delay irradiation) are not eligible. Patients presenting with visual disturbances by history or physical exam should have an ophthalmological exam and, if indicated, an MRI to determine optic nerve or retinal involvement.
Minimum age
1 Year
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
3/07/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
4/09/2020
Sample size
Target
Accrual to date
Final
16
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 0 0
Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 0 0
Royal Children's Hospital - Brisbane
Recruitment hospital [3] 0 0
Royal Children's Hospital, Melbourne - Melbourne
Recruitment hospital [4] 0 0
Sydney Children's Hospital - Sydney
Recruitment postcode(s) [1] 0 0
- Westmead
Recruitment postcode(s) [2] 0 0
- Brisbane
Recruitment postcode(s) [3] 0 0
- Melbourne
Recruitment postcode(s) [4] 0 0
- Sydney
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
District of Columbia
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Georgia
Country [6] 0 0
United States of America
State/province [6] 0 0
Illinois
Country [7] 0 0
United States of America
State/province [7] 0 0
Maryland
Country [8] 0 0
United States of America
State/province [8] 0 0
Massachusetts
Country [9] 0 0
United States of America
State/province [9] 0 0
Michigan
Country [10] 0 0
United States of America
State/province [10] 0 0
Minnesota
Country [11] 0 0
United States of America
State/province [11] 0 0
New York
Country [12] 0 0
United States of America
State/province [12] 0 0
North Carolina
Country [13] 0 0
United States of America
State/province [13] 0 0
Ohio
Country [14] 0 0
United States of America
State/province [14] 0 0
Oregon
Country [15] 0 0
United States of America
State/province [15] 0 0
Pennsylvania
Country [16] 0 0
United States of America
State/province [16] 0 0
Tennessee
Country [17] 0 0
United States of America
State/province [17] 0 0
Texas
Country [18] 0 0
United States of America
State/province [18] 0 0
Utah
Country [19] 0 0
United States of America
State/province [19] 0 0
Washington
Country [20] 0 0
United States of America
State/province [20] 0 0
Wisconsin
Country [21] 0 0
Canada
State/province [21] 0 0
Ontario
Country [22] 0 0
Canada
State/province [22] 0 0
Quebec
Country [23] 0 0
Canada
State/province [23] 0 0
Vancouver

Funding & Sponsors
Primary sponsor type
Other
Name
Therapeutic Advances in Childhood Leukemia Consortium
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Pfizer
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Susan Rheingold, MD
Address 0 0
Children's Hospital of Philadelphia
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT01614197