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A Pilot Study to Determine the Safety and Tolerability of Sirolimus Given With Hyper-CVAD Chemotherapy

Primary Purpose

Lymphoid Malignancies (New or Relapsed), Acute Lymphoblastic Leukemia, Burkitt Lymphoma

Status
Completed
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Hyper-CVAD
Sirolimus
Sponsored by
Sidney Kimmel Cancer Center at Thomas Jefferson University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphoid Malignancies (New or Relapsed) focused on measuring hyperCVAD, rapamycin, lymphoid malignancies, lymphoblastic leukemia, B and T cell, philadelphia chromosome negative, burkitt lymphoma, burkitt-type lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, adult t cell leukemia, adult t cell lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients must have a diagnosis of one of the following lymphoid malignancies (new or relapsed):

    • Acute Lymphoblastic Leukemia (B and T cell, Philadelphia Chromosome Negative)
    • Burkitt Lymphoma
    • Burkitt - type Lymphoma
    • Lymphoblastic Lymphoma
    • Mantle Cell Lymphoma
    • Adult T cell Leukemia/ lymphoma
  2. Patients must be >18 years old
  3. Patients must have an ECOG performance status of 0 or 1(see attachment 1).
  4. Patients must have a life expectancy of at least 4 weeks.
  5. Patients must be able to consume oral medication.
  6. Patients must have completed any radiotherapy four weeks prior to study entry, 0-2 weeks for local palliative XRT (small port).
  7. Patients must have recovered from the toxic effects of any prior chemotherapy to < grade 2 (except alopecia).
  8. Required initial laboratory values: Creatinine < or = 2.0mg/dL; total or direct bilirubin < or = 1.5mg/dL (if not due to the leukemia or lymphoma itself); SGPT(ALT) < or = 3xULN; glucose <200 mg/dL, negative pregnancy test for women with child-bearing potential.
  9. Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing.
  10. Patients may have had a prior stem cell transplant (autologous or allogeneic), however they may not have active GvHD, nor be on any immunosuppression

Exclusion Criteria:

  1. Patients must not be receiving any chemotherapy agents (except Hydroxyurea)
  2. Intrathecal ARA-C and intrathecal methotrexate are permissible (as they are not systemic and only isolated to the central nervous system).
  3. Patients must not be receiving growth factors, except for erythropoietin.
  4. Patients with a current second malignancy requiring systemic therapy, other than non-melanoma skin cancers, are not eligible.
  5. Patients with uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure, myocardial infarction within the past 6 months or serious uncontrolled cardiac arrhythmia are not eligible.

  6. Patients taking any of the following drugs while on-study are not eligible:

    1. Carbamazepine (e.g. Tegretol)
    2. Rifabutin (e.g. Mycobutin)
    3. Rifampin (e.g. Rifadin)
    4. Rifapentine (e.g. Priftin)
    5. St. John's Wort- may decrease the effects of sirolimus by decreasing the amount of sirolimus in the body
    6. Clarithromycin (e.g. Biaxin)
    7. Cyclosporin e.g. (Neorla or Sandimmune)
    8. Diltiazem (e.g. Cardizem)
    9. Erythromycin (e.g. Akne-Mycin, Ery-Tab)
    10. Itraconazole (e.g. Sporanox)
    11. Ketoconazole (e.g. Nizoral)
    12. Telithromycin (e.g. Ketek)
    13. Verapamil (e.g. Calan SR, Isoptin, Verelan)
    14. Voriconazole (e.g. VFEND) - May increase the effects of sirolimus by increasing the amount of this medicine in the body. [Cannot be taken within 72 hours prior to or subsequent to receiving rapamycin, but may be taken prior to or after the above time period]
    15. Tacrolimus (e.g. Prograf) - May cause liver transplant rejection or serious side effects in patients on sirolimus.
  7. Patients with known HIV positivity or AIDS-related illness are not eligible.
  8. Patients with other severe concurrent disease which in the judgment of the investigator would make the patient inappropriate for entry into this study are ineligible.
  9. Patients must not have evidence of cerebellar dysfunction or prior history of cerebellar dysfunction with Ara-C administration.
  10. Patients must not have received any investigational agents within 30 days of study entry.
  11. Patients must not be pregnant or breastfeeding. Pregnancy tests must be obtained for all females of child-bearing potential. Pregnant or lactating patients are ineligible for this study due to the unknown human fetal or teratogenic toxicities of rapamycin. Males or females of reproductive age may not participate unless they have agreed to use an effective contraceptive method.
  12. Patients who have uncontrolled infection are not eligible. Patients must have any active infections under control. Fungal disease must be stable for at least 2 weeks before study entry. Patients with bacteremia must have documented negative blood cultures prior to study entry.

Sites / Locations

  • University of Pennsylvania
  • Thomas Jefferson University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Hyper-CVAD and Sirolimus

Arm Description

Hyper-CVAD and Sirolimus

Outcomes

Primary Outcome Measures

Number of Participants With Count Recovery That Allows for Starting a Phase II Study to Evaluate Response Rates and Survival
This will be assessed by evaluating the tolerability of this regimen compared to historical controls who received Hyper-CVAD or Hyper-CVAD/ Rituximab regimens. The treatment will be designated feasible for an individual subject if in 80% of chemotherapy cycles the subject has count recovery that allows for starting the subsequent cycle by Day 28. Count recovery is defined as ANC (absolute neutrophil count) of > 0.5 x 10^9/L and platelet count > 50 x 10^9/L. Hyper-CVAD/Rapamycin will be deemed acceptable if it is feasible to administer in 80% or more of subjects.

Secondary Outcome Measures

Induction Mortality
Induction mortality. Hyper-CVAD/ Rapamycin will be considered acceptable if induction mortality does not exceed 31% in patients older than 60, or 15% in those younger than 60
Complete Response
To describe response rates to hyper-CVAD and sirolimus in adults with ALL and other aggressive lymphoid malignancies. Bone marrow (<5% blasts) with adequate bone marrow cellularity, no evidence of circulating blasts or extramedullary disease and normalization of peripheral blood counts except for platelets (neutrophil count =1,000/µL).

Full Information

First Posted
August 17, 2010
Last Updated
November 10, 2017
Sponsor
Sidney Kimmel Cancer Center at Thomas Jefferson University
Collaborators
American Society of Clinical Oncology
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1. Study Identification

Unique Protocol Identification Number
NCT01184885
Brief Title
A Pilot Study to Determine the Safety and Tolerability of Sirolimus Given With Hyper-CVAD Chemotherapy
Official Title
A Pilot Study of Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (Hyper-CVAD) With Sirolimus for the Treatment of Adult Acute Lymphoblastic Leukemia and Aggressive Lymphoid Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
November 2017
Overall Recruitment Status
Completed
Study Start Date
July 2010 (undefined)
Primary Completion Date
March 2011 (Actual)
Study Completion Date
April 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Cancer Center at Thomas Jefferson University
Collaborators
American Society of Clinical Oncology

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a pilot study, assessing the feasibility, safety and toxicity of an mTOR (mammalian target of Rapamycin) inhibitor (MTI), rapamycin, when administered with HyperCVAD (Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicine and Dexamethasone), with an ultimate goal to perform a phase II study to evaluate response rates and survival in adults with Acute Lymphoblastic Leukemia (ALL) and aggressive lymphoid malignancies.
Detailed Description
The primary objective of this trial is to characterize the feasibility, safety and tolerability of therapy with Hyper-CVAD and Rapamycin in adults with ALL and other aggressive lymphoid malignancies. This study will evaluate the effectiveness of Rapamycin given in combination with Hyper-CVAD during A treatment cycles, and Methotrexate and Cytarabine in B treatment cycles. Both cycles will also contain the drug Rituximab if the patient has a B cell type of leukemia or lymphoma. This combination of drugs are being studied to determine whether or not these drugs will have an effect in treating this disease. Current therapeutic regimens for induction of remission in ALL are broadly similar. There is no single best regimen for induction therapy. The hyper-CVAD regimen is of particular interest because it does not include asparaginase as part of the therapeutic regimen and the results of induction are similar to other published regimens. The HyperCVAD regimen with or without rituximab is also an accepted induction regimen for lymphoblastic lymphoma, Burkitt and Burkitt like lymphoma, Mantle Cell Lymphoma, and ALL in the elderly. The regimen has also been used as a salvage regimen in patients with the above diagnoses who have relapsed after another induction regimen. This trial will add a novel agent, an mTOR inhibitor (MTI), rapamycin, to act synergistically with the HyperCVAD regimen. This is a pilot study, assessing the feasibility, safety and toxicity of this regimen, with an ultimate goal to perform a phase II study to evaluate response rates and survival. This is a pilot study of the Hyper-CVAD regimen with Rapamycin for the treatment of adults with acute lymphoblastic leukemia or other aggressive lymphoid malignancies. The standard Hyper-CVAD regimen will be used, with the addition of the investigational agent, Rapamycin. Hyper-CVAD alone is one of the current standard induction and salvage regimens used to treat ALL and other aggressive lymphoid malignancies. Subjects included will have either de novo, relapsed, or refractory ALL or another aggressive lymphoid malignancy. Chemotherapy will consist of 4 'A' cycles alternating with 4 'B' cycles, every 21 days, or as count recovery allows (at least 14 days apart) as follows: 1A; 1B; 2A; 2B, 3A; 3B; 4A; 4B. This is dependent on white blood cell count recovery.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoid Malignancies (New or Relapsed), Acute Lymphoblastic Leukemia, Burkitt Lymphoma, Lymphoblastic Lymphoma, Mantle Cell Lymphoma, Adult T-cell Leukemia/Lymphoma
Keywords
hyperCVAD, rapamycin, lymphoid malignancies, lymphoblastic leukemia, B and T cell, philadelphia chromosome negative, burkitt lymphoma, burkitt-type lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, adult t cell leukemia, adult t cell lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Hyper-CVAD and Sirolimus
Arm Type
Experimental
Arm Description
Hyper-CVAD and Sirolimus
Intervention Type
Drug
Intervention Name(s)
Hyper-CVAD
Other Intervention Name(s)
Cytoxan, Endoxan, Neosar, Procytox, Revimmune, Cytophosphane, Oncovin, Leurocristine, Adriamycin, Hydroxydaunorubicin, MTX, Amethopterin
Intervention Description
Cycle A: Cyclophosphamide 300mg/m2 every 12 hours on days 3-5; Vincristine 2mg/day on days 6 and 13; Doxorubicin 50mg/m2 on day 6; Decadron 40mg/ day po on days 3-6 and 13-16; Methotrexate 12mg IT on day 4; Ara-C 100mg IT on day 9. Cycle B: Methotrexate 1000mg/m2 on day 3; Leucovorin 50mg every 6 hours starting 24 hours from the beginning of the MTX infusion until MTX levels are < 0.1 umol/L; Ara-C 3000mg/m2 every 12 hours on days 4 and 5; Methotrexate 12mg IT on day 4; Ara-C 100mg IT on day 9. Rituximab (if given) will be 375 mg/m2 on Days 3 and 13 of Cycle A and on Days 4 and 9 of cycle B, for a total of 8 doses over the first 4 courses.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamycin
Intervention Description
Sirolimus loading dose of 12mg on day 1 followed by a single daily dose of 4 mg/ day on days 2 through 7 (Cycle A) and on days 2 through 6 (Cycle B)
Primary Outcome Measure Information:
Title
Number of Participants With Count Recovery That Allows for Starting a Phase II Study to Evaluate Response Rates and Survival
Description
This will be assessed by evaluating the tolerability of this regimen compared to historical controls who received Hyper-CVAD or Hyper-CVAD/ Rituximab regimens. The treatment will be designated feasible for an individual subject if in 80% of chemotherapy cycles the subject has count recovery that allows for starting the subsequent cycle by Day 28. Count recovery is defined as ANC (absolute neutrophil count) of > 0.5 x 10^9/L and platelet count > 50 x 10^9/L. Hyper-CVAD/Rapamycin will be deemed acceptable if it is feasible to administer in 80% or more of subjects.
Time Frame
18 months
Secondary Outcome Measure Information:
Title
Induction Mortality
Description
Induction mortality. Hyper-CVAD/ Rapamycin will be considered acceptable if induction mortality does not exceed 31% in patients older than 60, or 15% in those younger than 60
Time Frame
18 months
Title
Complete Response
Description
To describe response rates to hyper-CVAD and sirolimus in adults with ALL and other aggressive lymphoid malignancies. Bone marrow (<5% blasts) with adequate bone marrow cellularity, no evidence of circulating blasts or extramedullary disease and normalization of peripheral blood counts except for platelets (neutrophil count =1,000/µL).
Time Frame
Every 21 days or as count recovery allows (at least 14 days apart) up to 24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have a diagnosis of one of the following lymphoid malignancies (new or relapsed): Acute Lymphoblastic Leukemia (B and T cell, Philadelphia Chromosome Negative) Burkitt Lymphoma Burkitt - type Lymphoma Lymphoblastic Lymphoma Mantle Cell Lymphoma Adult T cell Leukemia/ lymphoma Patients must be >18 years old Patients must have an ECOG performance status of 0 or 1(see attachment 1). Patients must have a life expectancy of at least 4 weeks. Patients must be able to consume oral medication. Patients must have completed any radiotherapy four weeks prior to study entry, 0-2 weeks for local palliative XRT (small port). Patients must have recovered from the toxic effects of any prior chemotherapy to < grade 2 (except alopecia). Required initial laboratory values: Creatinine < or = 2.0mg/dL; total or direct bilirubin < or = 1.5mg/dL (if not due to the leukemia or lymphoma itself); SGPT(ALT) < or = 3xULN; glucose <200 mg/dL, negative pregnancy test for women with child-bearing potential. Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing. Patients may have had a prior stem cell transplant (autologous or allogeneic), however they may not have active GvHD, nor be on any immunosuppression Exclusion Criteria: Patients must not be receiving any chemotherapy agents (except Hydroxyurea) Intrathecal ARA-C and intrathecal methotrexate are permissible (as they are not systemic and only isolated to the central nervous system). Patients must not be receiving growth factors, except for erythropoietin. Patients with a current second malignancy requiring systemic therapy, other than non-melanoma skin cancers, are not eligible. Patients with uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure, myocardial infarction within the past 6 months or serious uncontrolled cardiac arrhythmia are not eligible. Patients taking any of the following drugs while on-study are not eligible: Carbamazepine (e.g. Tegretol) Rifabutin (e.g. Mycobutin) Rifampin (e.g. Rifadin) Rifapentine (e.g. Priftin) St. John's Wort- may decrease the effects of sirolimus by decreasing the amount of sirolimus in the body Clarithromycin (e.g. Biaxin) Cyclosporin e.g. (Neorla or Sandimmune) Diltiazem (e.g. Cardizem) Erythromycin (e.g. Akne-Mycin, Ery-Tab) Itraconazole (e.g. Sporanox) Ketoconazole (e.g. Nizoral) Telithromycin (e.g. Ketek) Verapamil (e.g. Calan SR, Isoptin, Verelan) Voriconazole (e.g. VFEND) - May increase the effects of sirolimus by increasing the amount of this medicine in the body. [Cannot be taken within 72 hours prior to or subsequent to receiving rapamycin, but may be taken prior to or after the above time period] Tacrolimus (e.g. Prograf) - May cause liver transplant rejection or serious side effects in patients on sirolimus. Patients with known HIV positivity or AIDS-related illness are not eligible. Patients with other severe concurrent disease which in the judgment of the investigator would make the patient inappropriate for entry into this study are ineligible. Patients must not have evidence of cerebellar dysfunction or prior history of cerebellar dysfunction with Ara-C administration. Patients must not have received any investigational agents within 30 days of study entry. Patients must not be pregnant or breastfeeding. Pregnancy tests must be obtained for all females of child-bearing potential. Pregnant or lactating patients are ineligible for this study due to the unknown human fetal or teratogenic toxicities of rapamycin. Males or females of reproductive age may not participate unless they have agreed to use an effective contraceptive method. Patients who have uncontrolled infection are not eligible. Patients must have any active infections under control. Fungal disease must be stable for at least 2 weeks before study entry. Patients with bacteremia must have documented negative blood cultures prior to study entry.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Margaret Kasner, MD
Organizational Affiliation
Thomas Jefferson University
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Thomas Jefferson University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.JeffersonHospital.org
Description
Thomas Jefferson University Hospitals

Learn more about this trial

A Pilot Study to Determine the Safety and Tolerability of Sirolimus Given With Hyper-CVAD Chemotherapy

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