Clinical trial NCT03430791: Trial of Combination Tumor Treating Fields (TTF; Optune), Nivolumab Plus/Minus Ipilimumab for Recurrent Glioblastoma
Official title: A Phase I/II Trial of Combination Tumor Treating Fields, Nivolumab Plus/Minus Ipilimumab for Recurrent Glioblastoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Recurrent Glioblastoma
Keywords: recurrent glioblastoma
Lead sponsor: Baptist Health South Florida
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
name: NovoCure Ltd.
First posted: 2018-02-13
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is an open-label, phase II trial with two parallel arms, two-stage design and appropriate stopping rules for poor efficacy. Arm A will enroll participants without prior PD1/PDL1 checkpoint inhibitor, while Arm B will enroll participants with prior PD1/PDL1 checkpoint inhibitor. The investigator expect to enroll at least 30 (15 in each Arm) and a maximum of 60 (30 in each Arm) evaluable subjects. All subjects will receive tumor treating field (TTF) therapy plus nivolumab infusions for a maximum of 24 months, plus/minus concurrent ipilimumab for a maximum of 4 doses.
Primary purpose: TREATMENT

Brief summary: Phase I/II trial in which participants with recurrent glioblastoma will receive a combination of tumor treating fields(portable device), nivolumab with or without ipilimumab.

Detailed description: Phase I/II trial in which participants with recurrent glioblastoma will receive a combination of tumor treating fields(portable device), nivolumab with or without ipilimumab.

The NovoTTF200A (OptuneTM) device is worn continuously for a goal of 75% or more of the time, ranging from at least 18 hours daily uninterrupted or 22 hours daily with 2-3 days off monthly. Therapy is planned for approximately 24 months.

Infusions with nivolumab will start within 1 week of study start. Ipilimumab will either start with the second nivolumab infusion or at after tumor progression. Nivolumab is infused intravenously at 240 mg once every 2 weeks with or without ipilimumab for a maximum of 24 months. Ipilimumab is dosed at 1 mg/kg once every 6 weeks for a maximum of 4 doses (24 weeks). Infusions will continue until maximum doses are completed or there is confirmed tumor progression, intolerable adverse effects or withdrawal of consent.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed World Health Organization Grade IV glioblastoma with supratentorial distribution.
* Unequivocal evidence of progressive disease on contrast-enhanced brain CT or MRI as defined by Response Assessment in Neuro-Oncology (RANO) criteria, or documented recurrent glioblastoma on biopsy.
* Measurable disease based on RANO criteria.
* Prior therapies including radiation and temozolomide.
* Any number of recurrences are allowed. Resection of recurrent glioblastoma is not considered a prior treatment.
* From the projected start date of study treatment, the following periods must have elapsed: 4 weeks from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), or 4 weeks from any other antibodies or any other antineoplastic therapies.
* Must be at least 12 weeks from radiotherapy or progression outside of the high-dose radiation target volume or unequivocal evidence of progressive tumor on biopsy.
* All adverse events Grade \> 1 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must be resolved, except for alopecia.
* Karnofsky Performance Status (KPS) ≥ 60
* Adequate organ and marrow function as defined below, all screening labs should be performed within 14 days of treatment initiation:

  * absolute neutrophil count ≥ 1,000/mcL
  * platelets ≥100,000/mcL
  * hemoglobin \> 8.0 mg/dL
  * total bilirubin ≤ 2.0 x upper limit of normal
  * AST (SGOT)/ALT (SGPT) ≤ 2.5 × upper limit of normal
  * creatinine or creatinine clearance ≥ 60 mL/min/1.73 m2 for creatinine \>ULN
* Corticosteroid dose must be stable or decreasing for at least 5 days prior to enrollment.
* Nivolumab and ipilimumab are potentially teratogenic or abortifacient. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to entry and for the duration of study. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Male subjects should agree to use adequate method of contraception starting with the first dose through 7 months after the last dose of therapy.
* Brain CT or MRI within 14 days prior to start of study drug.
* Archival tissue for evaluation of correlative objectives (if available).
* Ability to understand and the willingness to provide written informed consent.

Exclusion Criteria:

* Infratentorial disease.
* Bevacizumab within 2 months of enrollment. Prior use of ipilimumab or other CTLA-4 inhibitor or prior TTFields.
* Tumors with known IDH1 (isocitrate dehydrogenase 1) or IDH2 mutations as determined by immunohistochemistry for the IDH1 R132H variant or by direct sequencing. IDH1/2-mutant gliomas have a prolonged overall survival rate compared to IDH1/2-wildtype gliomas, indicating distinct natural history.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab or ipilimumab or their excipients.
* Current or planned participation in a study of an investigational agent or using an investigational device.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
* Active or life-threatening infection requiring intravenous or \>2 weeks of systemic therapy.
* Prior stereotactic radiotherapy, convection enhanced delivery (CED) or brachytherapy requires a biopsy to confirm radiographic progression is consistent with progressive tumor and not treatment-related necrosis unless the recurrent lesion is outside of any prior high-dose radiation target volume or distant from the prior CED or brachytherapy site.
* There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, so breastfeeding must be discontinued by enrollment on study.
* Uncontrolled HIV or AIDS is not allowed. Patients with known history of HIV but with undetectable viral load on antiretroviral therapy are allowed.
* Congestive heart failure, myocardial infarction, or hemorrhagic/ischemic stroke in the last 3 months.
* Active illicit drug use or diagnosis of alcoholism
* Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer or other in situ malignancy that has undergone potentially curative therapy and/or with \>90% probability of survival beyond 5 years.
* Any surgery (not including minor diagnostic procedures such as lymph node biopsy) within 2 weeks of start of treatment. Incomplete recovery from any side effects of previous procedures is also exclusionary.
* Any significant autoimmune disorders expected to impact multiple or internal organs, excluding mild eczema or autoimmune thyroiditis treated with thyroidectomy and requiring systemic immunosuppressive or immunomodulatory therapy.
* Any implanted programmable cranial device, including reprogrammable ventriculoperitoneal shunt (VPS) or cochlear implants, that precludes use of TTFields (Optune) therapy.

Primary outcomes:
measure: Objective Response Rate According to Modified iRANO Criteria
timeFrame: 2 years
Secondary outcomes:
measure: Objective Response Rate (ORR) by Standard RANO Criteria
timeFrame: 2 years
measure: Progression Free Survival (PFS)
timeFrame: 2 years
measure: Number of Toxicities
timeFrame: Up to 2 years
measure: Rate of Treatment Compliance
timeFrame: Monthly for up to 2 years
measure: Discontinuation Rate of Any Component of Therapy
timeFrame: Up to 2 years
measure: Change in Quality of Life From Baseline Using the Functional Assessment of Cancer Therapy-Brain (FACT-Br)
timeFrame: Up to 2 years
measure: Change in Quality of Life From Baseline Using the Functional Assessment of Cancer Therapy-General (FACT-G)
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Miami
country: United States
facility: Miami Cancer Institute at Baptist Health, Inc.
state: Florida
Study officials:
affiliation: Miami Cancer Institute at Baptist Health, Inc.
name: Yazmin Odia
role: PRINCIPAL_INVESTIGATOR
References: