Clinical trial NCT01614197: A Trial of Temsirolimus With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphoblastic Leukemia, Acute, Childhood
Lymphoblastic Lymphoma
Peripheral T-cell Lymphoma
Keywords: Relapse
Lymphoblastic
Leukemia
Refractory
Temsirolimus
Acute
Childhood
Pediatric
ALL
NHL
LL
PTL
Lead sponsor: Therapeutic Advances in Childhood Leukemia Consortium
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2012-06-07
Enrollment: 16
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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).
Primary purpose: TREATMENT

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).

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 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.

Primary outcomes:
measure: Number of Patients That Experienced DLT During Cycle 1 of Therapy
timeFrame: Cycle 1 (a minimum of 4 weeks and a max of 8 weeks)
Secondary outcomes:
measure: Response Rate at the Completion of 1 Cycle of Study Treatment
timeFrame: Cycle 1 (a minimum of 4 weeks and a max of 8 weeks)
measure: Minimum Residual Disease (MRD) Levels Present at End of Cycle 1 Therapy in Patients
timeFrame: Cycle 1 (a minimum of 4 weeks and a max of 8 weeks)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: Orange
country: United States
facility: Children's Hospital Orange County
state: California
city: San Francisco
country: United States
facility: UCSF School of Medicine
state: California
city: Aurora
country: United States
facility: The Children's Hospital, University of Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Miami
country: United States
facility: University of Miami Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta, Emory University
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's Hospital
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Dana Farber
state: Massachusetts
city: Ann Arbor
country: United States
facility: C.S. Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Childrens Hospital & Clinics of Minnesota
state: Minnesota
city: New York
country: United States
facility: Children's Hospital New York-Presbyterian
state: New York
city: Charlotte
country: United States
facility: Levine Children's Hospital at Carolinas Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Rainbow Babies
state: Ohio
city: Columbus
country: United States
facility: Nationwide Childrens Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude
state: Tennessee
city: Dallas
country: United States
facility: University of Texas at Southwestern
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Children's Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Royal Children's Hospital, Melbourne
state: Victoria
city: Sydney
country: Australia
facility: Sydney Children's Hospital
city: Toronto
country: Canada
facility: Hospital for Sick Kids
state: Ontario
city: Montreal
country: Canada
facility: Sainte Justine University Hospital
state: Quebec
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Susan Rheingold, MD
role: STUDY_CHAIR
References: