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

Peripheral T-cell Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01614197
• Other study ID #: T2014-001
• Status: Completed
• Phase: Phase 1
• Start date: July 3, 2015
• Est. completion date: September 4, 2020

Study information

• Verified date: July 2023
• Source: Therapeutic Advances in Childhood Leukemia Consortium
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: September 4, 2020
• Est. primary completion date: December 15, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 21 Years

Eligibility

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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Lymphoblastic Leukemia, Acute, Childhood
• Lymphoblastic Lymphoma
• Lymphoma
• Lymphoma, Non-Hodgkin
• Lymphoma, T-Cell, Peripheral
• Peripheral T-cell Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Temsirolimus
Dose will be assigned at study entry. Give IV over 30 minutes on days 1 and 8.
• Etoposide
100 mg/m2 IV over 1-2 hours daily x 5 on Days 1-5.
• Cyclophosphamide
440 mg/m2 IV daily x 5 on Days 1-5 given over 30-60 minutes.
• 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
• 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
• 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

Locations

Country	Name	City	State
Australia	Royal Children's Hospital	Brisbane	Queensland
Australia	Royal Children's Hospital, Melbourne	Melbourne	Victoria
Australia	Sydney Children's Hospital	Sydney
Australia	Children's Hospital at Westmead	Westmead	New South Wales
Canada	Sainte Justine University Hospital	Montreal	Quebec
Canada	Hospital for Sick Kids	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver
United States	C.S. Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta, Emory University	Atlanta	Georgia
United States	The Children's Hospital, University of Colorado	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	Dana Farber	Boston	Massachusetts
United States	Levine Children's Hospital at Carolinas Medical Center	Charlotte	North Carolina
United States	Lurie Children's Hospital	Chicago	Illinois
United States	Rainbow Babies	Cleveland	Ohio
United States	Nationwide Childrens Hospital	Columbus	Ohio
United States	University of Texas at Southwestern	Dallas	Texas
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Texas Children's Hospital	Houston	Texas
United States	Childrens Hospital Los Angeles	Los Angeles	California
United States	St. Jude	Memphis	Tennessee
United States	University of Miami Cancer Center	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Childrens Hospital & Clinics of Minnesota	Minneapolis	Minnesota
United States	Children's Hospital New York-Presbyterian	New York	New York
United States	Children's Hospital Orange County	Orange	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Primary Children's	Salt Lake City	Utah
United States	UCSF School of Medicine	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Therapeutic Advances in Childhood Leukemia Consortium	Pfizer

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Patients That Experienced DLT During Cycle 1 of Therapy	The incidence of dose limiting toxicity (DLT) will be measured. The maximum tolerated dose will be the highest study dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy. All these analyses will be descriptive and exploratory and hypotheses generating in nature.	Cycle 1 (a minimum of 4 weeks and a max of 8 weeks)
Secondary	Response Rate at the Completion of 1 Cycle of Study Treatment	CR = Complete remission defined as attainment of bone marrow with <5% blasts with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (absolute neutrophil counts (ANC) > or = to 500/uL and platelet count > or = to 50,000 microliters) CRi = Complete remission with incomplete blood count recovery defined as attainment of bone marrow with >5% blasts with no evidence of circulating blasts or extramedullary disease but insufficient recovery of ANC < 500/uL or platelets < 50,000 microliters PR = partial remission defined as complete disappearance of circulating blasts and achievement of 5-25% blasts if greater than 25% blasts originally without new sites of extramedullary disease and with recovery of ANC.; SD = stable disease defined as not satisfying criteria for PD, or has recovery of ANC > or = to 500/uL and fails to qualify for CR, CRi, or PR PD = progressive disease defined as an increase of at least 25% in bone marrow leukemic cells	Cycle 1 (a minimum of 4 weeks and a max of 8 weeks)
Secondary	Minimum Residual Disease (MRD) Levels Present at End of Cycle 1 Therapy in Patients	MRD positive is defined as > or = to 0.1% MRD MRD negative is define as < 0.1% MRD; All these analyses will be descriptive and exploratory and hypotheses generating in nature.	Cycle 1 (a minimum of 4 weeks and a max of 8 weeks)