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A Study of Low Dose Bevacizumab With Conventional Radiotherapy Alone in Diffuse Intrinsic Pontine Glioma (LoBULarDIPG)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04250064
Recruitment Status : Recruiting
First Posted : January 31, 2020
Last Update Posted : March 23, 2020
Sponsor:
Information provided by (Responsible Party):
Tata Memorial Centre

Brief Summary:

In this study, the investigators are testing improvement in survival outcomes in DIPG patients when stratified with MR perfusion score and treated with the said protocol. Newly diagnosed DIPG patients will undergo MRI perfusion study in addition to the usual MRI at diagnosis and will be stratified into hyperperfused or hypoperfused tumours.

The hyperperfused patients will receive additional low dose Bevacizumab weekly with conventional standard radiotherapy.

The hypo-perfused patients will receive ultra-low-dose radiotherapy fractionation equivalent to conventional RT biological dose.


Condition or disease Intervention/treatment Phase
DIPG Drug: Bevacizumab Injection Radiation: Ultra-low-dose RT Phase 2

Detailed Description:

In tumours like Diffuse pontine glioma (DIPG), the diagnosis itself spells a death sentence for the child affected. The current standard treatment is conventionally fractionated daily radiation treatment for 6 weeks which benefits 80-90% patients with temporary improvement in neurological function which gives survival up to 8-10 months. With research over several decades, none of the altered fractionation radiotherapy or additional chemotherapy or targeted agents has shown a significant difference in outcomes.

The investigators propose to do an MRI perfusion study in addition to usual MRI at diagnosis and stratify them into hyperperfused or hypoperfused based on the criteria from the investigator's previously published institutional experience in DIPG. The hyperperfused patients will receive additional low dose a drug called Bevacizumab weekly with conventional standard radiotherapy. It is hypothesized that low dose Bevacizumab will decrease hypoxia and improve the efficacy of conventional radiotherapy and in turn improve outcomes.

The hypo-perfused patients will receive ultra-low-dose radiotherapy fractionation equivalent to conventional RT biological dose. As it is assumed that hypoperfused tumours are radioresistant, the investigator hypothesis that the ultra-low dose radiotherapy may overcome that radioresistance as seen in GBM adult patients and may improve outcomes.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Study of Low Dose Bevacizumab With Conventional Radiotherapy Alone in Diffuse Intrinsic Pontine Glioma
Actual Study Start Date : February 4, 2020
Estimated Primary Completion Date : February 2023
Estimated Study Completion Date : February 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

Arm Intervention/treatment
Experimental: Concurrent low-dose Bevacizumab
Low-dose concurrent Bevacizumab with standard radiotherapy
Drug: Bevacizumab Injection
Additional concurrent low-dose Bevacizumab with standard EBRT
Other Name: Concurrent low-dose Bevacizumab

Experimental: Ultra-low-dose RT
Ultra-low-dose RT
Radiation: Ultra-low-dose RT
Ultra-low-dose EBRT instead of standard dose RT




Primary Outcome Measures :
  1. Overall Survival [ Time Frame: median of 12 months from diagnosis ]
    Survival for the total enrolled patient population will calculated at the median follow up 12 months. This will be compared with historical data from TMH, international DIPG registry and SIOP DIPG registry for 12-month OS as 35%.


Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: 6 months, 12 months, 18 months from diagnosis ]
    Progression-free survival: at 6 months, 12 months, 18 months will be recorded for overall cohort and each arm separately at first progression only. For the purpose of the study, any patient with two or more new clinical signs of neurological deterioration in accordance with classical DIPG diagnosis with radiological progression of disease from any previous available imaging will be called progression.

  2. Adverse events [ Time Frame: From the time of intervention beginning, through the course of intervention, at the end of intervention and follow up 3 monthly to the date of precluding progression, or last known follow-up date, assessed for up to 2 years ]
    The documentation of highest grade of toxicity as per CTCAE v 4 and RTOG radiation toxicity.

  3. Steroid Use [ Time Frame: From the time of intervention beginning, through the course of intervention, at the end of intervention and follow up 3 monthly to the date of precluding progression, or last known follow-up date, assessed for up to 2 years ]
    Total duration of steroid use will be recorded

  4. Pattern of relapse [ Time Frame: from the date of enrollment on study to the last known follow-up date, assessed for up to 2 years ]
    local versus disseminated progression will be documented for each arm and overall cohort for the patients with available MRI at progression.

  5. Overall survival [ Time Frame: 6, 12 month and 18 months. ]
    Overall survival in each arm as well as for overall cohort will be recorded

  6. Compliance [ Time Frame: From the time of intervention beginning, through the course of intervention, till the planned intervention is completed to maximum of 10 weeks from beginning , which ever is earlier. ]
    Treatment intervention abandonment rates: number of patients not completing the planned intervention/treatment.

  7. Inconvenience rates [ Time Frame: From the time of intervention beginning, through the course of intervention, till the end of intervention or maximum of upto 10 weeks, which ever is earlier. ]
    average number of hours spent in hospital per day during the intervention phase.

  8. Quality of Life scores [ Time Frame: From date of accrual until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months ]
    The Qol scores will be calculated as per the routine OPD based collection of Health using utilities index (40 item standard questionnaire) and/or PedQol interviewer based scores.



Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Tumour Diagnosis: Newly diagnosed non-disseminated treatment naïve DIPG by classic clinical AND radiographic finding.
  2. Age: Patient must be 3 to 18 years of age at the time of diagnosis.
  3. Performance Score: KPS > 12 y/o >/= 50 or LPS for < 12y >/= 50 assessed at enrollment.
  4. Participants must have normal organ and marrow function as defined below within two weeks prior to enrollment:

    1. Hematological: Absolute neutrophil count > 1,000/mcL, Platelets> 100,000/mcL (transfusion independent), HB > 8gm/dL (can be transfused)
    2. Hepatic: Total bilirubin < 1.5 times the upper limit of normal; alanine aminotransferase [SGPT (ALT)] and aspartate aminotransferase [SGOT (AST)] < 5 times the institutional upper limit of normal.
    3. Renal: Serum creatinine which is less than 1.5x the upper limit of institutional normal for age or Glomerular Filtration Rate (GFR) > 70 ml/min/1.73m2.; The absence of clinically significant proteinuria as defined by a screening early morning urine (first sample) dipstick urinalysis of < 2.
    4. Normal coagulation profile
  5. Post-Biopsy patients allowed, but should not have evidence of haemorrhage greater than 0.5cm intracranially and should satisfy this criterion within two to four weeks of biopsy to start treatment in Arm 1 if designated as per perfusion study along with satisfying other criteria as applicable. For arm 2, there will be no restriction other than the usual criteria.
  6. No contra-indication for GA for MRI
  7. Would not need GA for RT in the hypofractionated subgroup (due to logistics).
  8. Ability to understand and the willingness to sign a written informed consent document by the parent or guardian and assent by the child as applicable and as per institutional policy.

Exclusion Criteria:

Other than those mentioned above,

  1. Surgical Procedures: Patients who have had major surgery should not receive the first dose of BVZ until 28 days after major surgery or Serious or Non-Healing Wounds
  2. Patients with uncontrolled systemic hypertension/ Proteinuria with a urine protein (albumin)/creatinine ratio of ≥1.0.
  3. Thrombosis: Patients must not have been previously diagnosed with a deep venous or arterial thrombosis (including pulmonary embolism), and must not have a known thrombophilic condition.
  4. Allergies: Patients with a history of allergic reaction to Chinese hamster ovary cell products, or other recombinant human antibodies.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04250064


Contacts
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Contact: Rahul Krishnatry, Dr 022-24177000 ext 7028 krishnatry@gmail.com

Locations
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India
Tata Memorial Hospital Recruiting
Mumbai, Maharashtra, India, 400012
Contact: Dr Rahul Krishnatry, MD    022-24177000 ext 6023    krishnatry@gmail.com   
Sponsors and Collaborators
Tata Memorial Centre
Investigators
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Principal Investigator: Rahul Krishnatry, Dr Tata Memorial Hospital
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Responsible Party: Tata Memorial Centre
ClinicalTrials.gov Identifier: NCT04250064    
Other Study ID Numbers: 3201
First Posted: January 31, 2020    Key Record Dates
Last Update Posted: March 23, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Bevacizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors