Clinical trial NCT04250064: A Study of Low Dose Bevacizumab With Conventional Radiotherapy Alone in Diffuse Intrinsic Pontine Glioma
Official title: A Study of Low Dose Bevacizumab With Conventional Radiotherapy Alone in Diffuse Intrinsic Pontine Glioma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: DIPG
Lead sponsor: Tata Memorial Centre
Sponsor class: OTHER
First posted: 2020-01-31
Enrollment: 40
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Overall Survival
timeFrame: median of 12 months from diagnosis
Secondary outcomes:
measure: Progression-free survival
timeFrame: 6 months, 12 months, 18 months from diagnosis
measure: Adverse events
timeFrame: 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
measure: Steroid Use
timeFrame: 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
measure: Pattern of relapse
timeFrame: from the date of enrollment on study to the last known follow-up date, assessed for up to 2 years
measure: Overall survival
timeFrame: 6, 12 month and 18 months.
measure: Compliance
timeFrame: 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.
measure: Inconvenience rates
timeFrame: 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.
measure: Quality of Life scores
timeFrame: 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
Other outcomes:
Locations:
city: Mumbai
country: India
facility: Tata Memorial Hospital
state: Maharashtra
Study officials:
affiliation: Tata Memorial Hospital
name: Rahul Krishnatry, Dr
role: PRINCIPAL_INVESTIGATOR
References: