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

NCT01614197 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: T2014-001
• Study Type: interventional
• Target: 16
• Locations: 3 countries
• Sites: 32

Brief 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).

Conditions

Lymphoblastic Leukemia, Acute, Childhood; Lymphoblastic Lymphoma; Peripheral T-cell Lymphoma

Keywords

Relapse; Lymphoblastic; Leukemia; Refractory; Temsirolimus; Acute; Childhood; Pediatric; ALL; NHL; LL; PTL

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Response Rate at the Completion of 1 Cycle of Study Treatment

  Cycle 1 (a minimum of 4 weeks and a max of 8 weeks)

• Minimum Residual Disease (MRD) Levels Present at End of Cycle 1 Therapy in Patients

  Cycle 1 (a minimum of 4 weeks and a max of 8 weeks)

Study Arms (4)

Dose Level 1

EXPERIMENTAL

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.

Drug: Temsirolimus; Drug: Etoposide; Drug: Cyclophosphamide; Drug: Methotrexate; Drug: Hydrocortisone; Drug: Cytarabine

Dose Level 2

EXPERIMENTAL

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.

Drug: Temsirolimus; Drug: Etoposide; Drug: Cyclophosphamide; Drug: Methotrexate; Drug: Hydrocortisone; Drug: Cytarabine

Dose Level 3

EXPERIMENTAL

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.

Drug: Temsirolimus; Drug: Etoposide; Drug: Cyclophosphamide; Drug: Methotrexate; Drug: Hydrocortisone; Drug: Cytarabine

Dose Level 4

EXPERIMENTAL

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.

Drug: Temsirolimus; Drug: Etoposide; Drug: Cyclophosphamide; Drug: Methotrexate; Drug: Hydrocortisone; Drug: Cytarabine

Interventions

Temsirolimus DRUG

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

Also known as: Torisel, CCI-779

Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4

Etoposide DRUG

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

Also known as: Toposar, VePesid, VP-16

Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4

Cyclophosphamide DRUG

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

Also known as: Cytoxan, Neosar

Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4

Methotrexate DRUG

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

Also known as: MTX, Amethopterin, Trexall

Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4

Hydrocortisone DRUG

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

Also known as: Hydrocortisone sodium succinate, Solu-cortef

Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4

Cytarabine DRUG

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

Also known as: Cytosine arabinoside, Ara-C, Cytosar

Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Therapeutic Advances in Childhood Leukemia Consortium: lead
• Pfizer: collaborator

Study Sites (32)

Childrens Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Children's Hospital Orange County

Orange, California, United States

Location

UCSF School of Medicine

San Francisco, California, 94143-0106, United States

Location

The Children's Hospital, University of Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, United States

Location

University of Miami Cancer Center

Miami, Florida, 33136, United States

Location

Children's Healthcare of Atlanta, Emory University

Atlanta, Georgia, 30322, United States

Location

Lurie Children's Hospital

Chicago, Illinois, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21231, United States

Location

Dana Farber

Boston, Massachusetts, 02215, United States

Location

C.S. Mott Children's Hospital

Ann Arbor, Michigan, 48109-0914, United States

Location

Childrens Hospital & Clinics of Minnesota

Minneapolis, Minnesota, 55404-4597, United States

Location

Children's Hospital New York-Presbyterian

New York, New York, 10032, United States

Location

Levine Children's Hospital at Carolinas Medical Center

Charlotte, North Carolina, 28203, United States

Location

Rainbow Babies

Cleveland, Ohio, 44106, United States

Location

Nationwide Childrens Hospital

Columbus, Ohio, United States

Location

Oregon Health and Science University

Portland, Oregon, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

St. Jude

Memphis, Tennessee, 38105-3678, United States

Location

University of Texas at Southwestern

Dallas, Texas, 75235, United States

Location

Cook Children's Medical Center

Fort Worth, Texas, 76104, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Primary Children's

Salt Lake City, Utah, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Location

Children's Hospital at Westmead

Westmead, New South Wales, Australia

Location

Royal Children's Hospital

Brisbane, Queensland, Australia

Location

Royal Children's Hospital, Melbourne

Melbourne, Victoria, Australia

Location

Sydney Children's Hospital

Sydney, Australia

Location

Hospital for Sick Kids

Toronto, Ontario, Canada

Location

Sainte Justine University Hospital

Montreal, Quebec, Canada

Location

British Columbia Children's Hospital

Vancouver, Canada

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, T-Cell, Peripheral; Recurrence; Leukemia

Interventions

temsirolimus; Etoposide; Cyclophosphamide; Methotrexate; Hydrocortisone; hydrocortisone hemisuccinate; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, T-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Limitations and Caveats

All these analyses will be descriptive and exploratory and hypotheses generating in nature.

Results Point of Contact

• Title: Roy Leong
• Organization: Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL)

rleong@chla.usc.edu

323-361-5132

Study Officials

• Susan Rheingold, MD

  Children's Hospital of Philadelphia

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study follows a standard 3+3 patient cohort escalation design, as described below: 1. Three patients are entered at the first dose level 2. If 0/3 experiences DLT at a given dose level, then the dose is escalated to the next higher level, if a higher dose level exists, and three patients are enrolled. If a higher dose level does not exists, up to three more patients are accrued at the same dose level. 3. If 1/3 experiences DLT at current dose, then up to three more patients are accrued at the same dose level. 4. If 2 or more DLTs are observed in a three-patient or six-patient cohort at a given dose level, then the MTD has been exceeded, dose escalation will be stopped, and up to three additional patients will be enrolled at the next lower dose level, if a lower dose level exists (unless six patients have already been treated at that prior dose).

Study Record Dates

• First Submitted: May 18, 2012
• First Posted: June 7, 2012
• Study Start: July 3, 2015
• Primary Completion: December 15, 2019
• Study Completion: September 4, 2020
• Last Updated: July 27, 2023
• Results First Posted: July 27, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

CA (3); AU (4); US (25)