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Phase I/Comparative Randomized Phase II Trial of TRC105 Plus Bevacizumab Versus Bevacizumab in Bevacizumab-Naive Patients With Recurrent Glioblastoma Multiforme


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Diffuse Astrocytoma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Oligodendroglioma, Recurrent Adult Brain Tumor

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Trial Information

Phase I/Comparative Randomized Phase II Trial of TRC105 Plus Bevacizumab Versus Bevacizumab in Bevacizumab-Naive Patients With Recurrent Glioblastoma Multiforme


PRIMARY OBJECTIVES:

I. To establish a maximum tolerated dose (MTD) of TRC105 combined with bevacizumab in this
patient population. (Phase I) II. To assess the safety and adverse events of TRC105 in
combination with bevacizumab in this patient population. (Phase II) III. To determine the
efficacy of TRC105 in combination with bevacizumab in recurrent glioblastoma as measured by
progression-free survival and compare it with the efficacy of bevacizumab alone in this
patient population. (Phase II)

SECONDARY OBJECTIVES:

I. To assess the proportion of patients who are progression free at 6 months, treated with
TRC105 in combination with bevacizumab as compared to bevacizumab alone. (Phase II) II. To
assess the overall survival of patients treated with TRC105 in combination with bevacizumab
compared to bevacizumab alone. (Phase II) III. To compare the impact of the treatment on the
patients quality of life (QOL) using the EORTC Quality of Life QLQ-C15-PAL and QLQ-BN20
Patient Questionnaires. (Phase II) IV. To estimate patient recommendations for study
participation to others using the Was It Worth It (WIWI) Questionnaire. (Phase II)

TERTIARY OBJECTIVES:

I. To evaluate the pharmacokinetics of TRC105. (Phase I) II. To evaluate the immunogenicity
of TRC105. (Phase I) III. To determine the relationship between tumor biomarkers,
circulating biomarkers of vascular response and vascular endothelial growth factor
(VEGF)/VEGFR single-nucleotide polymorphism (SNPs) in predicting efficacy and/or toxicity of
treatment. (Phase II) IV. To assess the utility of magnetic resonance imaging (MRI) imaging
including apparent diffusion coefficient (ADC) as a predictor of response and survival.
(Phase II) V. To assess the utility of dynamic contrast enhanced (DCE) MRI as a predictor of
response to bevacizumab with or without TRC105. (Phase II)

OUTLINE: This is a multicenter, dose-escalation, phase I study of TRC105 followed by a
randomized phase II study.

Phase I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1 and
TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of course 2 and all
subsequent courses. Courses repeat every 14 days in the absence of disease progression or
unacceptable toxicity.

Phase II: Patients are stratified according to age (> 70 vs =< 70) and resection at
recurrence (yes vs no). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive bevacizumab IV over 30-90 minutes on day 1 and TRC105 IV over 1-4
hours on days 8 and 11 of course 1 and days 1 and 8 of course 2 and all subsequent courses.
Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.


Inclusion Criteria:



- Histological confirmation of grade 3 or 4 glioma, including astrocytoma,
oligodendroglioma, and mixed gliomas, as determined by preregistration central
pathology review (Phase I)

- Histological confirmation of glioblastoma multiforme (grade 4 astrocytoma) as
determined by pre-registration central pathology review (Phase II)

- Gliosarcomas and other grade 4 astrocytoma variants (e.g., giant cell) are
eligible

- Evidence of tumor progression by magnetic resonance imaging (MRI) or computed
tomography (CT) scan following radiation therapy or following the most recent
anti-tumor therapy

- Patients who have had surgical treatment at recurrence are eligible if they had
a resection with measurable or non-measurable residual disease on postoperative
imaging or if there is imaging evidence of disease progression as compared to
the first postoperative scan

- Measurable or evaluable disease by gadolinium MRI or contrast CT scan

- Patients who have had a gross total resection (GTR) are eligible on the basis of
evaluable disease

- Blood and tissue samples for correlative research purposes required (Phase II)

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Platelet count >= 100,000/mm^3

- White blood cells (WBC) >= 3,000/mL

- Hemoglobin >= 10.0 g/dL; Note: This level may be reached by transfusion

- Total bilirubin =< institutional upper limit of normal (ULN)

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =<
2 times ULN

- Creatinine =< ULN

- Life expectancy >= 12 weeks

- Negative serum pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

- Urine protein creatinine (UPC) ratio < 1; Note: Urine protein must be screened by
urine analysis for urine protein creatinine (UPC) ratio; for UPC ratio >= 1.0,
24-hour urine protein must be obtained and the level should be < 1,000 mg for
registration

- Fixed or decreasing dose of corticosteroids (or no corticosteroids) >= 7 days prior
to registration

- Calculated glomerular filtration rate (GFR) must be >= 60 ml/min; GFR will be
calculated as needed per institutional guidelines

- Any number of prior chemotherapy regimens for recurrent disease (Phase I)

- =< 1 chemotherapy or other non-antiangiogenic regimen for recurrent disease
(Phase II)

- Last dose of bevacizumab >= 2 weeks prior to registration (Phase I); Note: prior
exposure to bevacizumab is not allowed for Phase II

- Surgery >= 4 weeks prior to registration

- Completion of radiation therapy >= 12 weeks prior to registration and prior
chemotherapy >= 4 weeks prior to registration (>= 6 weeks from nitrosourea-containing
regimens)

- Small molecular cell cycle inhibitors >= 2 weeks from registration

- Ability to provide informed written consent

- Ability to complete questionnaire(s) by themselves or with assistance

- Willing to return to enrolling institution for follow-up

- Willing to discontinue use of aspirin or medications that inhibit platelet function
>= 10 days prior to registration;

- Aspirin at doses greater than 325 mg/day must be discontinued >= 10 days prior
to registration and avoided through the study Note: Nonsteroidal
antiinflammatory drug (NSAID) medications are recommended in place of aspirin;
if NSAIDs or aspirin are used, H-2 blockers and proton pump inhibitor (PPI)
medications are recommended

- Willing to provide mandatory blood and tissue samples for correlative research
purposes (Phase I and II)

Exclusion Criteria:

- Any of the following because this study involves investigational agents whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception throughout the duration of the study and for at least 6 months
after treatment has ended

- Prior hypersensitivity to bevacizumab or toxicity requiring discontinuation of
bevacizumab (Phase I)

- Any prior exposure to any vascular endothelial growth factor (VEGF) or VEGF inhibitor
including, but not limited to, bevacizumab, cediranib, vandetanib, sunitinib,
pazopanib, aflibercept, or sorafenib (Phase II)

- No prior hypersensitivity to Chinese hamster ovarycell products or other recombinant
human antibodies

- Prior hypersensitivity to triptan derivatives

- Other active malignancy =< 3 years prior to registration; exceptions: nonmelanotic
skin cancer or carcinoma-in-situ of the cervix; Note: If there is a history of prior
malignancy, they must not be receiving other specific treatment (other than hormonal
therapy) for their cancer

- Uncontrolled infection

- Immunocompromised patients or patients known to be human immunodeficiency virus (HIV)
positive and currently receiving combination antiretroviral therapy; Note:
HIV-positive patients receiving combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions with bevacizumab; in
addition, these patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy; appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated positive, but without
clinical evidence of an immunocompromised state, are eligible for this trial

- Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
adverse events of the prescribed regimens

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, or psychiatric illness/social situations that would limit compliance with
study requirements

- History of hypertensive crisis or hypertensive encephalopathy

- Clinically significant cardiovascular disease defined as follows:

- Inadequately controlled hypertension (i.e., systolic blood pressure (SBP)> 160
mm Hg and/or diastolic blood pressure (DBP) > 90 mm Hg despite antihypertensive
therapy)

- History of cerebrovascular accident (CVA) within 6 months

- Myocardial infarction or unstable angina within 6 months

- New York Heart Association classification II, III, or IV cardiovascular disease

- Serious and inadequately controlled cardiac arrhythmia

- Significant vascular disease (i.e., aortic aneurysm, history of aortic
dissection)

- Clinically significant peripheral vascular disease

- Evidence or history of bleeding diathesis (greater than normal risk of bleeding,
i.e., Hereditary Hemorrhagic Telangiectasia type I [HHT-1]) or coagulopathy in the
absence of therapeutic anti-coagulation or any hemorrhage/bleeding event > grade 3
within 4 weeks prior to registration

- Receiving any other investigational agent that would be considered as a treatment for
the primary neoplasm

- Prior treatment with TRC105

- Serious or non-healing wound, active ulcer, or untreated bone fracture

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess =< 6 months prior to registration

- History of invasive procedures defined as follows:

- Major surgical procedure, open biopsy, or significant traumatic injury =< 28
days prior to registration

- Anticipation of need for major surgical procedures during the study

- Core biopsy =< 7 days prior to registration

- History of significant vascular disease (i.e., aortic aneurysm requiring surgical
repair, or recent peripheral arterial thrombosis) within 6 months prior to
registration

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of TRC105 combined with bevacizumab based on the incidence of dose-limiting toxicity (DLT) (Phase I)

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Evanthia Galanis

Investigator Role:

Principal Investigator

Investigator Affiliation:

North Central Cancer Treatment Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-01989

NCT ID:

NCT01648348

Start Date:

November 2012

Completion Date:

Related Keywords:

  • Adult Anaplastic Astrocytoma
  • Adult Anaplastic Oligodendroglioma
  • Adult Diffuse Astrocytoma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Oligodendroglioma
  • Recurrent Adult Brain Tumor
  • Astrocytoma
  • Brain Neoplasms
  • Glioblastoma
  • Oligodendroglioma
  • Gliosarcoma

Name

Location

Memorial Sloan Kettering Cancer CenterNew York, New York  10021
Mayo ClinicRochester, Minnesota  55905
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
University of VirginiaCharlottesville, Virginia  22908
North Central Cancer Treatment GroupRochester, Minnesota  55905
UCSF-Mount ZionSan Francisco, California  94115