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A Trial of Temsirolimus With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma

Information source: Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Lymphoblastic Leukemia, Acute, Childhood; Lymphoblastic Lymphoma; Peripheral T-cell Lymphoma

Intervention: Temsirolimus (Drug); Etoposide (Drug); Etoposide phosphate (Drug); Cyclophosphamide (Drug); Methotrexate (Drug); Hydrocortisone (Drug); Cytarabine (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: Therapeutic Advances in Childhood Leukemia Consortium

Official(s) and/or principal investigator(s):
Susan Rheingold, MD, Study Chair, Affiliation: Children's Hospital of Philadelphia

Overall contact:
Jeannette van der Giessen, Phone: 323-361-8725, Email: jvandergiessen@chla.usc.edu

Summary

This is a phase I study of temsirolimus (Torisel) combined with dexamethasone, cyclophosphamide and etoposide in patients with relapsed acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL) or peripheral T-cell lymphoma (PTL).

Clinical Details

Official 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

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: The dose of temsirolimus that can be safely given with etoposide and cyclophosphamide.

Secondary outcome:

The response rate after treatment.

Responsiveness of patient lymphoblasts to mTOR inhibition using in-vitro and in-vivo pharmacodynamic (PD) assessments.

Minimal residual disease (MRD) levels present at end of cycle 1 therapy in patients with bone marrow involvement.

Detailed description: Studies have shown that mTOR inhibitors (MTI) inhibit growth of pre-B and T-cell ALL cell lines in vitro and in ALL xenograft models. The MTI temsirolimus was chosen for use in this study due to its weekly intravenous dosing, its more predictable blood levels, and availability of a single-agent pediatric MTD and its sustained biologic effect due to conversion to sirolimus. This study will determine the maximum tolerated dose of temsirolimus that can given in combination with dexamethasone, cyclophosphamide and etoposide in relapsed ALL, LL or PTL. A standard 3-patient cohort dose-escalation design will be used. Response to treatment will be evaluated. Biology tests will be done to evaluate minimal residual disease (MRD), temsirolimus' effect on glucocorticoid resistance, and mTOR inhibition.

Eligibility

Minimum age: 1 Year. Maximum age: 21 Years. Gender(s): Both.

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

- Patients must have relapsed or refractory acute lymphoblastic leukemia (ALL) with

greater than or equal to 25% blasts in the bone marrow (M3). OR

- Patients may have an M2 marrow (greater than or equal to 5% to < 25% blasts) with an

extramedullary site of relapse; including CNS 2 and CNS 3.

- Refractory disease defined as no more than 1 prior failed salvage attempt following

the current relapse, or no more than 2 additional treatment cycles after initial induction failure in newly diagnosed patients. 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, if other sites of involvement.

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 must have had 2 or more prior therapeutic attempts defined as:

- Relapse after going into remission from re-induction for the first or subsequent

relapse (ie: 2nd , 3rd, 4th…relapse), or

- Patients with lymphoma may have refractory disease after first or greater relapse and

a single re-induction attempt. 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 42 days after the completion of any type of immunotherapy, e. g. tumor vaccines. or chimeric antigen receptor T cell (CART) therapy. 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 7 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. Study specific limitations on prior therapy: Patient may not have received therapy with an mTOR inhibitor. 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.

- 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. 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.

Locations and Contacts

Jeannette van der Giessen, Phone: 323-361-8725, Email: jvandergiessen@chla.usc.edu

Sydney Children's Hospital, Sydney, Australia; Not yet recruiting

Children's Hospital at Westmead, Westmead, NSW, Australia; Not yet recruiting

British Columbia Children's Hospital, Vancouver, Canada; Not yet recruiting

Childrens Hospital Los Angeles, Los Angeles, California 90027, United States; Recruiting
Paul S. Gaynon, MD, Principal Investigator

Children's Hospital Orange County, Orange, California, United States; Not yet recruiting

UCSF School of Medicine, San Francisco, California 94143-0106, United States; Not yet recruiting
Steven DuBois, MD, Principal Investigator

The Children's Hospital, University of Colorado, Aurora, Colorado 80045, United States; Not yet recruiting
Lia Gore, MD, Principal Investigator

Children's National Medical Center, Washington, District of Columbia, United States; Not yet recruiting

University of Miami Cancer Center, Miami, Florida 33136, United States; Not yet recruiting
John Goldberg, MD, Principal Investigator

Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia, United States; Not yet recruiting
Melinda Pauly, MD, Principal Investigator

Lurie Children's Hospital, Chicago, Illinois, United States; Not yet recruiting
Nobuko Hijiya, MD, Principal Investigator

Johns Hopkins University, Baltimore, Maryland, United States; Not yet recruiting
Pat Brown, MD, Principal Investigator

Dana Farber, Boston, Massachusetts, United States; Not yet recruiting
Lewis Silverman, MD, Principal Investigator

C.S. Mott Children's Hospital, Ann Arbor, Michigan 48109-0914, United States; Not yet recruiting
Raymond Hutchinson, MD, Principal Investigator

Childrens Hospital & Clinics of Minnesota, Minneapolis, Minnesota 55404-4597, United States; Not yet recruiting
Bruce Bostrom, MD, Principal Investigator
Yoav Messinger, MD, Principal Investigator

Children's Hospital New York-Presbyterian, New York, New York 10032, United States; Not yet recruiting
Maria Luisa Sulis, MD, Principal Investigator

Levine Children's Hospital at Carolinas Medical Center, Charlotte, North Carolina 28203, United States; Not yet recruiting
Javier Oesterheld, MD
Javier Oesterheld, MD, Principal Investigator

Rainbow Babies, Cleveland, Ohio, United States; Not yet recruiting
Joe Matloub, MD

Nationwide Childrens Hospital, Columbus, Ohio, United States; Not yet recruiting
Robyn Dennis, MD, Principal Investigator

Hospital for Sick Kids, Toronto, Ontario, Canada; Not yet recruiting

Oregon Health and Science University, Portland, Oregon, United States; Not yet recruiting
Bill Chang, MD, Principal Investigator

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States; Not yet recruiting
Sue Rheingold, MD, Principal Investigator

Sainte Justine University Hospital, Montreal, Quebec, Canada; Not yet recruiting
Henrique Bittencourt, MD

Royal Children's Hospital, Brisbane, Queensland, Australia; Not yet recruiting

St. Jude, Memphis, Tennessee 38105-3678, United States; Not yet recruiting
Sima Jeha, MD
Sima Jeha, MD, Principal Investigator

Vanderbilt Children's Hospital, Nashville, Tennessee, United States; Not yet recruiting
Howard Katzenburg, MD, Principal Investigator

University of Texas at Southwestern, Dallas, Texas, United States; Not yet recruiting

Cook Children's Medical Center, Forth Worth, Texas 76104, United States; Not yet recruiting
Kenneth Heym, MD, Principal Investigator

Primary Children's, Salt Lake City, Utah, United States; Not yet recruiting
Elizabeth Raetz, MD

Royal Children's Hospital, Melbourne, Melbourne, Victoria, Australia; Not yet recruiting

Seattle Children's Hospital, Seattle, Washington 98105, United States; Not yet recruiting
Todd Cooper, MD, Principal Investigator

Medical College of Wisconsin, Milwaukee, Wisconsin, United States; Not yet recruiting
Mike Burke, Principal Investigator

Additional Information

Starting date: March 2015
Last updated: March 17, 2015

Page last updated: August 23, 2015

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