A Study to Compare Vincristine to Sirolimus for Treatment of High Risk Vascular Tumors

NCT02110069

Last updated date
Study Location
Lucille Packard Children's Hospital Stanford
Palo Alto, California, 94304, United States
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Kaposiform Hemangioendothelioma (KHE), Kasabach-Merritt Syndrome, Tufted Angioma
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
0-31
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- Diagnosis: All patients must have one of the following vascular anomalies as determined by clinical, radiologic and histologic criteria (when possible). Biopsy strongly recommended (but not required) with suggested immunostains: CD34, PROX-1 or D240, Glut-1 and MIB-1.

1. Kaposiform Hemangioendotheliomas

2. Tufted angioma

High Risk Stratification: In addition to the above diagnosis, all of the following criteria need to be met:

a. Kasabach Merritt Syndrome defined at a platelet counts less than 50,000 K/µl and/or fibrinogen level < 100 mg/dl at the time of diagnosis.

- Age: Patients must be 0 - 31 years of age at the time of study entry. Enrollment includes patients of both genders and all ethnic groups.

- Organ function requirements:

1. Adequate liver function defined as:

1. Total bilirubin ≤ 1.5 x ULN for age, and

2. SGPT (ALT) ≤ 5 x ULN for age, and

3. Serum albumin >/= 2 g/dL.

4. Fasting LDL cholesterol of <160 mg/dL

5. Fasting triglyceride <400 mg/dl

2. Adequate Bone Marrow Function defined as:

1. Peripheral absolute neutrophil count (ANC) >/= 1000/uL

2. Hemoglobin >/= 8.0 g/dL (may receive RBC transfusions)

3. No Platelet requirement

3. Adequate Renal Function Defined as:

1. A serum creatinine based on age as follows:

Age (Years) Maximum Serum Creatinine (mg/dL)

- 5 0.8 6 to ≤10 1.0 11 to ≤15 1.2 >15 1.5

2. Urine protein to creatinine ratio (UPC) < 0.3 g/l

- Performance Status: Karnofsky >/= 50 (≥16 years of age) and Lansky >/= 50 for patients <16 years of age.

- Prior therapy

1. Patients who have undergone surgical resection or interventional radiology procedures for disease control are eligible if they meet all inclusion criteria after surgery/procedure

2. Surgery: At least 2 weeks since undergoing any major surgery

3. Radiation: > 6 months from involved field radiation

4. Prior vincristine therapy is permitted. Patients may also have received up to 2 doses of vincristine prior to randomization.

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- Concurrent severe and/or uncontrolled medical disease that could compromise
participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension,
severe infection, severe malnutrition, chronic liver or renal disease, active upper GI
tract ulceration).


- Patients who require medications that are strong inhibitors/inducers CYP3A4 enzyme
activity, including anticonvulsants, (Appendix II) to control concurrent medical
conditions are not eligible. Patients who discontinue use of prohibited medications
with a one week washout prior to start of study treatment are eligible.


- Known history of HIV seropositivity or known immunodeficiency. Testing is not required
unless a condition is suspected.


- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of sirolimus (e.g. ulcerative disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A
gastric tube or nasogastric tube is allowed.


- Females who are pregnant or breast feeding.


- Males or females of reproductive potential may not participate unless they have agreed
to use an effective contraceptive method during the period they are receiving the
study drug and for 3 months thereafter. Abstinence is an acceptable method of birth
control. Females of childbearing potential will be given a pregnancy test within 7
days prior to administration of study treatment and must have a negative urine or
serum pregnancy test.


- Patients who have received prior treatment with an mTOR inhibitor.


- Patients unwilling or unable to comply with the protocol or who in the opinion of the
investigator may not be able to comply with the safety monitoring requirements of the
study.


- Patients who currently have an uncontrolled infection, defined as receiving
intravenous antibiotics.

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Kaposiform Hemangioendothelioma (KHE), Kasabach-Merritt Syndrome, Tufted AngiomaA Study to Compare Vincristine to Sirolimus for Treatment of High Risk Vascular Tumors
NCT02110069
  1. Palo Alto, California
  2. Atlanta, Georgia
  3. Baltimore, Maryland
  4. Boston, Massachusetts
  5. Cincinnati, Ohio
  6. Houston, Texas
  7. Milwaukee, Wisconsin
ALL GENDERS
0+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE A Study to Compare Vincristine to Sirolimus for Treatment of High Risk Vascular Tumors
Official Title  ICMJE A Randomized Phase 2 Study of Vincristine Versus Sirolimus to Treat High Risk Kaposiform Hemangioendothelioma (KHE).
Brief Summary

In this research study we want to learn more about which treatment works better for patients diagnosed with a vascular tumor called Kaposiform Hemangioendothelioma (KHE) or other high risk vascular tumors such as Tufted Angioma (TA). In these tumors, the blood cells that help your blood clot called platelets become trapped in the tumor causing swelling, pain, and bruising. Vascular tumors can be life threatening. There are few medical treatments that will work to shrink the vascular tumor. Some doctors will use steroids and vincristine to try and shrink vascular tumors.

In this research study, the study doctor will compare two different drugs to see which one will work better to help shrink your vascular tumor. One of the drugs is vincristine. Vincristine is approved by the Food and Drug Administration (FDA) to treat people with cancer. Vincristine is used to stop the abnormal cells from growing such as cells that make up blood vessels.

The other drug to be used in this study is sirolimus. Sirolimus is currently approved by the Food and Drug Administration (FDA) to prevent transplanted organ rejection. Sirolimus is not approved by the FDA for treatment of vascular abnormalities and is considered experimental. Sirolimus belongs to a class of drugs call 'mTOR inhibitors'. mTOR (mammilian target of rapamycin) helps cells to grow and may also help blood vessels to grow in a more normal fashion. Sirolimus is currently being tested in patients with vascular tumors and cancer. In vascular tumors, we hope sirolimus will stop the blood vessel growth.

Funding Source: FDA - OOPD (Office of Orphan Products Development)

Detailed Description

Kaposiform hemangioendotheliomas (KHE) are extremely rare life threatening tumors which can be associated with Kasabach-Merritt Phenomenon consisting of profound thrombocytopenia and hypofibrinogenemia causing a significant risk of bleeding and an associated mortality rate as high as 20% to 30%. Despite the severity of potential complications, we lack uniform guidelines for the treatment and response to treatment of children and young adults with these tumors. KHE patients have been treated with a multitude of aggressive drug regimens without prospective evaluation of response or safety. Presently, vincristine is considered the standard of practice. We have treated a subset of these patients on study SIR-DA-0901 (FDA Grant# 5RO1FD003712-01). This study is a phase II trial assessing the efficacy and safety of sirolimus for the treatment of complicated vascular anomalies. Although the numbers are small, the response has been extremely promising with excellent tolerability. There is pre-clinical and clinical data supporting the essential regulatory function of the PI3 kinase/AKT/mTOR pathway in vascular growth and organization which suggests a therapeutic target for patients with complicated vascular anomalies. The overall goal of this trial is to objectively assess the efficacy of sirolimus compared to vincristine for the treatment of patients with high risk KHE.

Hypothesis: Sirolimus treatment for children and young adults with Kaposiform hemangioendotheliomas will be more effective than vincristine, assessed by time to response in an induction period and provide equivalent safety parameters.

Study Rationale We propose a multi-center, phase II trial with participation from 8 sites. The study will consist of two phases. The first of these is an initial induction phase in which vincristine and steroids will be compared to sirolimus and steroids. Response in the induction phase will be assessed as time to hematologic response. At the end of induction phase, cross over can occur if there is failure to respond. Part 2 is a maintenance phase which will be 1 year in length. Continued safety and efficacy data will be collected during maintenance and there will be cross over at any time for patients who lose their response following induction. Failure will be defined as worsening of hematological parameters on two separate laboratory evaluations at any time during maintenance or if they meet the definition of progressive disease following response assessments. Formal response in maintenance will be evaluated by imaging studies, functional assessment, and quality of life as per study SIR-DA-0901. Present therapies are very limited and new therapies are desperately needed for this devastating disease. Based on our preliminary data, there is a very good rationale for sirolimus therapy in KHE patients and so a phase II trial is urgently needed to determine if this therapy is to become the new standard of care for KHE patients.

Our secondary aims will be addressing biomarker analysis. There are limited studies describing the biology of these tumors. Per study SIR-DA-0901 there is some preliminary data indicating the importance of VEGF-C and other upregulated markers in the mTor pathway. This needs to be further investigated especially in KHE patients. Furthermore there are no clear objective measurements to determine response data.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Kaposiform Hemangioendothelioma (KHE)
  • Kasabach-Merritt Syndrome
  • Tufted Angioma
Intervention  ICMJE
  • Drug: Vincristine
    Vincristine dose dependent upon weight. Weekly for 2 months (Induction); Weekly 2 months; every 2 weeks for next 5 months; every 3 weeks for 5 months (Maintenance)
    Other Names:
    • Oncovin
    • Vincasar® PFS
    • Vincrex
  • Drug: Sirolimus
    Continuous dosing to maintain trough level of 10-15ng/ml.
    Other Name: Rapamune
Study Arms  ICMJE
  • Active Comparator: Vincristine

    Induction phase: participants assigned to vincristine will receive vincristine weekly at a dose of 0.05mg/kg/dose IV (for participants less than 10kg) or a dose of 1.5 mg/m2/dose (for participants greater than 10kg) for 2 months.

    Maintenance: if participants continue to receive vincristine weekly for 2 months, every 2 weeks for 5 months and every 3 weeks for 5 months.

    Intervention: Drug: Vincristine
  • Experimental: Sirolimus

    Sirolimus will be administered at a dose of 0.8mg/m2/dose twice a day on a continuous dosing schedule throughout the trial for participants randomized to Sirolimus or for participants who fail vincristine may cross-over to the sirolimus arm.

    Sirolimus trough levels will be maintained between 10-15 ng/ml.

    Intervention: Drug: Sirolimus
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: April 8, 2014)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2026
Estimated Primary Completion Date September 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis: All patients must have one of the following vascular anomalies as determined by clinical, radiologic and histologic criteria (when possible). Biopsy strongly recommended (but not required) with suggested immunostains: CD34, PROX-1 or D240, Glut-1 and MIB-1.

    1. Kaposiform Hemangioendotheliomas
    2. Tufted angioma

High Risk Stratification: In addition to the above diagnosis, all of the following criteria need to be met:

a. Kasabach Merritt Syndrome defined at a platelet counts less than 50,000 K/µl and/or fibrinogen level < 100 mg/dl at the time of diagnosis.

  • Age: Patients must be 0 - 31 years of age at the time of study entry. Enrollment includes patients of both genders and all ethnic groups.
  • Organ function requirements:

    1. Adequate liver function defined as:

      1. Total bilirubin ? 1.5 x ULN for age, and
      2. SGPT (ALT) ? 5 x ULN for age, and
      3. Serum albumin >/= 2 g/dL.
      4. Fasting LDL cholesterol of <160 mg/dL
      5. Fasting triglyceride <400 mg/dl
    2. Adequate Bone Marrow Function defined as:

      1. Peripheral absolute neutrophil count (ANC) >/= 1000/uL
      2. Hemoglobin >/= 8.0 g/dL (may receive RBC transfusions)
      3. No Platelet requirement
    3. Adequate Renal Function Defined as:

      1. A serum creatinine based on age as follows:

        Age (Years) Maximum Serum Creatinine (mg/dL)

        • 5 0.8 6 to ?10 1.0 11 to ?15 1.2 >15 1.5
      2. Urine protein to creatinine ratio (UPC) < 0.3 g/l
  • Performance Status: Karnofsky >/= 50 (?16 years of age) and Lansky >/= 50 for patients <16 years of age.
  • Prior therapy

    1. Patients who have undergone surgical resection or interventional radiology procedures for disease control are eligible if they meet all inclusion criteria after surgery/procedure
    2. Surgery: At least 2 weeks since undergoing any major surgery
    3. Radiation: > 6 months from involved field radiation
    4. Prior vincristine therapy is permitted. Patients may also have received up to 2 doses of vincristine prior to randomization.

Exclusion Criteria:

  • Concurrent severe and/or uncontrolled medical disease that could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration).
  • Patients who require medications that are strong inhibitors/inducers CYP3A4 enzyme activity, including anticonvulsants, (Appendix II) to control concurrent medical conditions are not eligible. Patients who discontinue use of prohibited medications with a one week washout prior to start of study treatment are eligible.
  • Known history of HIV seropositivity or known immunodeficiency. Testing is not required unless a condition is suspected.
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sirolimus (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A gastric tube or nasogastric tube is allowed.
  • Females who are pregnant or breast feeding.
  • Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during the period they are receiving the study drug and for 3 months thereafter. Abstinence is an acceptable method of birth control. Females of childbearing potential will be given a pregnancy test within 7 days prior to administration of study treatment and must have a negative urine or serum pregnancy test.
  • Patients who have received prior treatment with an mTOR inhibitor.
  • Patients unwilling or unable to comply with the protocol or who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
  • Patients who currently have an uncontrolled infection, defined as receiving intravenous antibiotics.
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE up to 31 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02110069
Other Study ID Numbers  ICMJE SIR-DA-1202
1R01FD004363-01A1 ( U.S. FDA Grant/Contract )
2013-2339 ( Other Identifier: CCHMC IRB )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD:No
Responsible Party Denise Martin Adams, Boston Children's Hospital
Study Sponsor  ICMJE Boston Children's Hospital
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Principal Investigator:Denise Adams, MDBoston Children's Hospital
PRS Account Boston Children's Hospital
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP