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

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ClinicalTrials.gov Identifier: NCT01184885
Recruitment Status : Completed
First Posted : August 19, 2010
Results First Posted : January 3, 2014
Last Update Posted : December 18, 2017
Sponsor:
Collaborator:
American Society of Clinical Oncology
Information provided by (Responsible Party):
Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University )

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Lymphoid Malignancies (New or Relapsed)
Acute Lymphoblastic Leukemia
Burkitt Lymphoma
Lymphoblastic Lymphoma
Mantle Cell Lymphoma
Adult T-cell Leukemia/Lymphoma
Interventions Drug: Hyper-CVAD
Drug: Sirolimus
Enrollment 7
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Hyper-CVAD and Sirolimus
Hide Arm/Group Description

Hyper-CVAD and Sirolimus

Hyper-CVAD : - 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.

Sirolimus : 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)

Period Title: Overall Study
Started 7
Completed 7
Not Completed 0
Arm/Group Title Hyper-CVAD and Sirolimus
Hide Arm/Group Description

Hyper-CVAD and Sirolimus

Hyper-CVAD : - 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.

Sirolimus : 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)

Overall Number of Baseline Participants 7
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants
<=18 years
0
   0.0%
Between 18 and 65 years
6
  85.7%
>=65 years
1
  14.3%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 7 participants
41.68  (18.94)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants
Female
2
  28.6%
Male
5
  71.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 7 participants
7
1.Primary Outcome
Title Number of Participants With Count Recovery That Allows for Starting a Phase II Study to Evaluate Response Rates and Survival
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Hyper-CVAD and Sirolimus
Hide Arm/Group Description:

Hyper-CVAD and Sirolimus

Hyper-CVAD : - Cycle A: Cyclophosphamide 300mg/m^2 every 12 hours on days 3-5; Vincristine 2mg/day on days 6 and 13; Doxorubicin 50mg/m^2 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/m^2 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/m^2 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/m^2 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.

Sirolimus : 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)

Overall Number of Participants Analyzed 7
Measure Type: Number
Unit of Measure: participants
7
2.Secondary Outcome
Title Induction Mortality
Hide 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
Outcome Measure Data Not Reported
3.Secondary Outcome
Title Complete Response
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Hyper-CVAD and Sirolimus
Hide Arm/Group Description:

Hyper-CVAD and Sirolimus

Hyper-CVAD : - 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.

Sirolimus : 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)

Overall Number of Participants Analyzed 7
Measure Type: Number
Unit of Measure: participants
4
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Hyper-CVAD and Sirolimus
Hide Arm/Group Description

Hyper-CVAD and Sirolimus

Hyper-CVAD : - 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.

Sirolimus : 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)

All-Cause Mortality
Hyper-CVAD and Sirolimus
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Hyper-CVAD and Sirolimus
Affected / at Risk (%) # Events
Total   6/7 (85.71%)    
Blood and lymphatic system disorders   
Febrile neutropenia  5/7 (71.43%)  8
Hypotension  2/7 (28.57%)  2
General disorders   
Fever  1/7 (14.29%)  1
Speech impairment  1/7 (14.29%)  1
Face pain  1/7 (14.29%)  1
Immune system disorders   
Gram negative sepsis  1/7 (14.29%)  1
Septic shock  1/7 (14.29%)  1
Infections and infestations   
Infection  2/7 (28.57%)  2
Nervous system disorders   
Ataxia  1/7 (14.29%)  1
Respiratory, thoracic and mediastinal disorders   
Shortness of breath  1/7 (14.29%)  1
Adult respiratory distress syndrome  1/7 (14.29%)  1
Skin and subcutaneous tissue disorders   
Edema  1/7 (14.29%)  1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Hyper-CVAD and Sirolimus
Affected / at Risk (%) # Events
Total   7/7 (100.00%)    
Blood and lymphatic system disorders   
Hyponatremia  1/7 (14.29%)  1
Positive blood culture  2/7 (28.57%)  3
Low platelets  1/7 (14.29%)  1
Low hemoglobin  1/7 (14.29%)  1
Pulse oxygen dropped  1/7 (14.29%)  1
Hypertension  2/7 (28.57%)  3
Anemia  1/7 (14.29%)  1
Pancytopenia  2/7 (28.57%)  3
Hypophosphatemia  1/7 (14.29%)  1
Neutropenia  1/7 (14.29%)  2
Lactic acidosis  1/7 (14.29%)  1
Hyperglycemia  1/7 (14.29%)  1
Hypokalemia  1/7 (14.29%)  1
Cardiac disorders   
Tachycardia  5/7 (71.43%)  11
Irregular heartbeat  1/7 (14.29%)  1
Eye disorders   
Blurred vision  1/7 (14.29%)  1
Eye pain  1/7 (14.29%)  2
Double vision  1/7 (14.29%)  1
Unable to move right eye  1/7 (14.29%)  1
Dry eyes  1/7 (14.29%)  1
Eye conjunctival redness  1/7 (14.29%)  1
Eyes appear uncoordinated  1/7 (14.29%)  1
Gastrointestinal disorders   
Dyspepsia  1/7 (14.29%)  1
Gastric reflux  2/7 (28.57%)  2
Stomach upset  2/7 (28.57%)  2
Diarrhea  5/7 (71.43%)  9
Gas/bloating  2/7 (28.57%)  2
Decreased bowel sounds  1/7 (14.29%)  1
General disorders   
Shoulder pain  1/7 (14.29%)  1
Abdominal pain  4/7 (57.14%)  5
Weight gain  2/7 (28.57%)  2
Fatigue  7/7 (100.00%)  15
Constipation  2/7 (28.57%)  4
Extremity swelling  1/7 (14.29%)  1
Itching  4/7 (57.14%)  4
Weakness  7/7 (100.00%)  10
Bad taste in mouth  1/7 (14.29%)  1
Nightmares  1/7 (14.29%)  1
Blood in stool  1/7 (14.29%)  1
Weight loss  2/7 (28.57%)  3
Sweats  4/7 (57.14%)  7
Chest pain  4/7 (57.14%)  6
Opacified left maxillary sinus  1/7 (14.29%)  1
Back pain  4/7 (57.14%)  4
Sinusitis  1/7 (14.29%)  1
Neutropenic fever  3/7 (42.86%)  5
Chills  5/7 (71.43%)  9
Nausea  6/7 (85.71%)  11
Abdominal ascites  1/7 (14.29%)  1
Gingivitis  1/7 (14.29%)  1
Insomnia  4/7 (57.14%)  4
Cough  4/7 (57.14%)  7
Stiff neck  2/7 (28.57%)  2
Congestion  1/7 (14.29%)  1
Fever  5/7 (71.43%)  9
Vomiting  4/7 (57.14%)  5
Post nasal drip  1/7 (14.29%)  1
Nosebleed  4/7 (57.14%)  6
Hypoxia  2/7 (28.57%)  4
Lightheadedness  2/7 (28.57%)  2
Alopecia  4/7 (57.14%)  4
Poor appetite  5/7 (71.43%)  5
Tooth problem  2/7 (28.57%)  2
Mouth sores  1/7 (14.29%)  1
Headache  4/7 (57.14%)  9
Speech impairment  1/7 (14.29%)  1
Throat pain  1/7 (14.29%)  1
Lower abductor pain  1/7 (14.29%)  1
Trouble sleeping  3/7 (42.86%)  3
Taste alteration  1/7 (14.29%)  1
Hip pain  1/7 (14.29%)  1
Cold  1/7 (14.29%)  1
Sinus congestion  2/7 (28.57%)  2
Bone pain  3/7 (42.86%)  3
Sore throat  2/7 (28.57%)  2
Wrist pain  1/7 (14.29%)  1
Ankle pain  1/7 (14.29%)  1
Agitation  2/7 (28.57%)  2
Rigidity  1/7 (14.29%)  1
Difficulty swallowing  1/7 (14.29%)  1
Dizziness  2/7 (28.57%)  2
Puffy face  1/7 (14.29%)  1
Swollen ankles  1/7 (14.29%)  1
Mouth/throat discomfort  1/7 (14.29%)  1
Rectal pain  1/7 (14.29%)  1
Abnormal gait  1/7 (14.29%)  1
Jaw pain  2/7 (28.57%)  2
Leg pain  1/7 (14.29%)  1
Soft tissue swelling  1/7 (14.29%)  1
Achiness  1/7 (14.29%)  1
Sinus headache  1/7 (14.29%)  1
Soreness of tongue  1/7 (14.29%)  1
Stomach pain  1/7 (14.29%)  1
Mucositis  1/7 (14.29%)  1
Bleeding from PICC site  1/7 (14.29%)  1
Transfusion reaction  1/7 (14.29%)  1
Elevated bilirubin  1/7 (14.29%)  2
Bleeding from IV site  1/7 (14.29%)  1
Fall  1/7 (14.29%)  1
Anal incontinence  1/7 (14.29%)  1
Oral bleeding  1/7 (14.29%)  1
Rib pain  1/7 (14.29%)  1
Volume overload  1/7 (14.29%)  1
Abdominal tenderness  1/7 (14.29%)  1
Infections and infestations   
Infection  3/7 (42.86%)  4
Respiratory infection  1/7 (14.29%)  1
Metabolism and nutrition disorders   
Anorexia  3/7 (42.86%)  4
Musculoskeletal and connective tissue disorders   
Muscle pain/tightness  2/7 (28.57%)  2
Increased troponins  1/7 (14.29%)  1
Nervous system disorders   
Numbness/tingling  3/7 (42.86%)  4
Neuropathy  4/7 (57.14%)  6
Choreiform movement  1/7 (14.29%)  1
Psychiatric disorders   
Anxiety  4/7 (57.14%)  4
Confusion  3/7 (42.86%)  4
Mood alteration  2/7 (28.57%)  2
Psychosis  2/7 (28.57%)  2
Catatonia  1/7 (14.29%)  1
Depression  1/7 (14.29%)  1
Delirium  1/7 (14.29%)  1
Renal and urinary disorders   
Nocturia  3/7 (42.86%)  3
Urinary incontinence  1/7 (14.29%)  1
Urinary frequency  1/7 (14.29%)  1
Decreased urine output  1/7 (14.29%)  1
Autodiuresis/polyuria  1/7 (14.29%)  1
Hematuria  1/7 (14.29%)  1
Urinary retention  2/7 (28.57%)  2
Respiratory, thoracic and mediastinal disorders   
Shortness of breath  5/7 (71.43%)  8
Pleural effusion  2/7 (28.57%)  2
Tachypnea  1/7 (14.29%)  1
Wheezing  1/7 (14.29%)  1
Absent breath sounds  1/7 (14.29%)  1
Skin and subcutaneous tissue disorders   
Edema  5/7 (71.43%)  10
Rash  6/7 (85.71%)  12
Abscess  2/7 (28.57%)  2
Dry skin  1/7 (14.29%)  1
Facial flushing  2/7 (28.57%)  2
Erythema  1/7 (14.29%)  1
Groin nodule  1/7 (14.29%)  1
Hyperpigmented circumscribed areas on scalp  1/7 (14.29%)  1
Blister  1/7 (14.29%)  1
Jaundice  1/7 (14.29%)  1
Petechiae  1/7 (14.29%)  1
Vascular disorders   
Phlebitis  1/7 (14.29%)  1
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Margaret Kasner, MD
Organization: Thomas Jefferson University
Phone: 215-955-8874
EMail: Margaret.Kasner@jefferson.edu
Layout table for additonal information
Responsible Party: Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University )
ClinicalTrials.gov Identifier: NCT01184885     History of Changes
Other Study ID Numbers: 09G.474
2009-35 ( Other Identifier: CCRRC )
First Submitted: August 17, 2010
First Posted: August 19, 2010
Results First Submitted: November 13, 2013
Results First Posted: January 3, 2014
Last Update Posted: December 18, 2017