Feasibility of Individualized Therapy for Recurrent GBM

• ClinicalTrials.gov Identifier: NCT03681028
• Recruitment Status: Active, not recruiting
• First Posted: September 21, 2018
• Last Update Posted: May 3, 2021
• Sponsor: Jennifer Clarke
• Information provided by (Responsible Party): Jennifer Clarke, University of California, San Francisco

Study Description

Brief Summary:

The current study will test the ability and likelihood of successfully implementing individualized combination treatment recommendations for adult patients with surgically-resectable recurrent glioblastoma in a timely fashion. Collected tumor tissue and blood will be examined using a new diagnostic testing called University of California, San Francisco (UCSF) 500 Cancer Gene Panel which is done at the UCSF Clinical Cancer Genomics Laboratory. The UCSF 500 Cancer Gene Panel will help identify genetic changes in the DNA of a patient's cancer, which helps oncologists improve treatment by identifying targeted therapies.

Condition or disease	Intervention/treatment	Phase
Recurrent Glioblastoma	Drug: Individualized therapy	Phase 1

Detailed Description:

This is a pilot, single-institution, single cohort, non-randomized open-label study to assess feasibility of implementing an individualized treatment regimen in patients with surgical recurrent GBM. Patients are not stratified according to demographic or treatment-related parameters. Patients must have recurrent glioblastoma treated with appropriate tumor treatment including radiation therapy at initial diagnosis. Surgery must be clinically indicated and patients must be candidates for tumor resection at UCSF.

The goal of the current study is to build upon prior results by confirming the feasibility of actually implementing patient-specific drug regimens in a rapid, clinically-relevant timetable. We will also assess for efficacy, safety, and response outcomes of these patient-specific regimens, to generate preliminary data that would support a larger trial assessing efficacy of such an approach.

Resected tumor tissue and blood will be examined using Next Generation Sequencing (NGS) UCSF 500 Cancer Gene Panel at the UCSF Clinical Cancer Genomics Laboratory and Whole genome and RNA sequencing. The clinical report generated from the NGS UCSF 500 panel will be provided to a study-specific Tumor Board who will generate an individualized treatment recommendation based on the report. The individualized treatment regimen potentially will include up to 4 re-purposed, off-the-shelf, FDA-approved targeted agents. The Board will identify the expected/anticipated drug-drug interactions and anticipated additional toxicities of the combination of therapies. The treating physician is given the report, discusses the suggested treatment options with the patient, and initiates treatment, ideally within 28 calendar days (and no later than 35 calendar days) after surgery. Treatment will continue until tumor progression.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Study Testing Feasibility of Individualized Therapy for Recurrent Glioblastoma
• Actual Study Start Date: December 19, 2018
• Actual Primary Completion Date: March 15, 2021
• Estimated Study Completion Date: January 31, 2026

Arms and Interventions

Arm

Intervention/treatment

Individualized therapy; Study treatment for a given patient will consist of a regimen chosen from agents implicated in critical molecular signaling pathways and/or from signature-based predictions of drug efficacy. All agents are listed in the current pharmacopoeia for human use, but will differ amongst individual subjects. The study treatment will consist of up to 4 FDA approved drugs that have known dosing. This study is not only looking at 4 drugs. It is selecting up to 4 drugs per patient but the drugs chosen can be any FDA-approved drug. Therefore, it is not possible to pre-specify the medications.

Drug: Individualized therapy; For a given proposed individualized combination of drugs the first priority to establish doses will be to identify the same combination of drugs in a peer-reviewed journal article or presented as a reviewed abstract.; When a proposed individualized combination of drugs has not previously been reported, the process to establish doses will be to then identify individual members of the proposed combination that have been used in combination with other cytotoxic agents similar to those being considered for combination therapy.; When a proposed individualized combination of drugs has no available combination data, dosing guidelines will start with the FDA-approved package insert recommended dose.

Outcome Measures

Primary Outcome Measures :

1. Percentage of patients who have successfully initiated therapy [ Time Frame: Up to 35 days after surgery ]
   Feasibility of implementing a truly personalized tumor treatment drug regimen for patients with surgically resectable recurrent glioblastoma is defined as the percentage of patients who have successfully initiated therapy based on their individualized treatment regimen within 35 days following surgical resection of recurrent tumor.

Secondary Outcome Measures :

1. Incidence of treatment-related Adverse Events (AEs) [ Time Frame: Up to 1 year ]
   Incidence of treatment-related AEs, grades 3-5 using NCI CTCAE v5.0 either due to individual treatment or combination treatment regimen
2. Progression-Free Survival (PFS) at 6 months [ Time Frame: 6 months ]
   PFS at 6 months is defined as the percentage of participants who have neither progressed nor died within 6 months after the first dose of individual treatment or combination treatment regimen. PFS at 6 months will be assessed by (modified) Response assessment in neuro-oncology criteria (RANO) and estimated using Kaplan Meier method.
3. Progression-Free Survival (PFS) [ Time Frame: Up to 5 years. ]
   PFS period is defined as the number of days from start of individual treatment or combination treatment regimen to disease progression or death. The PFS days of patient groups will be estimated using Kaplan-Meier method to show median progression-free period (days when 50% patients remain progression-free).
4. Overall survival (OS) [ Time Frame: Up to 5 years ]
   Overall survival is defined as the length of time from start of individual treatment or combination treatment regimen until date of death. For the participants who were alive at the end of study or lost to follow-up, overall survival will be censored on the last date when participants were known to be alive. OS will be estimated using the Kaplan-Meier method.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patient age must be >= 18 years
2. Patients must understand and provide written informed consent and Health Insurance Portability and Accountability Act of 1996 (HIPAA) authorization authorization prior to initiation of any study-specific procedures
3. Patients must have recurrence of histologically-proven glioblastoma or gliosarcoma, World Health Organization (WHO) grade IV that is surgically resectable.
4. The patient's surgeon thinks that they can resect at least 500 mg of tumor.
5. Patient must have Karnofsky Performance Scale (KPS) score >=70
6. Patient must have an estimated life expectancy ≥ 3 months
7. Patients may enroll independent of number of prior therapies or cumulative doses of prior therapies, but must have received appropriate prior therapy for GBM at time of initial diagnosis, including radiation therapy.

8. Patient must have adequate bone marrow function, renal function, and hepatic function as defined below:

   Adequate bone marrow function:

   1. absolute neutrophil count (ANC) >= 1,500/μL
   2. Platelets >= 100,000/μL

   Adequate hepatic function:

   1. total bilirubin <= 1.5x institutional upper limit of normal
   2. Aspartate aminotransferase (AST) /serum glutamic-oxaloacetic transaminase (SGOT) <= 2.5x institutional upper limit of normal
   3. Alanine aminotransferase (ALT) / serum glutamic-pyruvic transaminase (SGPT) <= 2.5x institutional upper limit of normal

   Adequate renal function:

   a. creatinine <= 1.5x institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m2

9. Must be able to undergo MRI scans for tumor evaluation.

10. Women of child-bearing potential must have a negative pregnancy test (urine or serum) within 7 days prior to surgery.

    The effects of study drugs, either individually or their combination on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation and for 3 months after completion of study drug administration. The use of adequate contraception may be longer than 3 months depending on the drugs used and the FDA-approved labeling in cases of recommendation for contraception. Adequate contraception may include hormonal contraception, barrier method (condom, contraceptive sponge, diaphragm or ring), intrauterine device (IUD), tubal ligation, vasectomy and abstinence. Should a woman become pregnant (or suspect that she is pregnant) while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of study drug administration. Patient must not be a woman who is currently pregnant, due to the potential for teratogenic or abortifacient effects of study drugs, either alone or in combination. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with study drugs, lactating women who are breastfeeding should discontinue breastfeeding if the mother is treated with any study drug.

11. Patients must not have New York Heart Association (NYHA) Grade II or greater congestive heart failure
12. Patients must not have history of myocardial infarction or unstable angina within 12 months prior to study enrollment.

Exclusion Criteria:

1. Patient who has been treated with any chemotherapy or radiotherapy ≤4 weeks prior to date of study registration. Exceptions to this include: must be ≥ 23 days from last dose of temozolomide (TMZ), must be ≥ 6 weeks from last dose of nitrosurea.
2. Patient who has not recovered to grade 1 or baseline from the adverse effects of prior radiotherapy or chemotherapy.
3. Patient who is < 12 weeks from initial course of radiation
4. Patients with multifocal tumor, primarily infratentorial or posterior fossa tumor, or leptomeningeal dissemination of tumor.
5. Patient with any other active malignancy besides GBM, excluding non-melanomatous skin cancer, or carcinoma in situ of the cervix, prostate, or breast, unless patient has been disease-free/in remission for >=2 years prior to date of study enrollment
6. Patients known to be HIV-positive. HIV testing is not required for study participation.
7. Uncontrolled concurrent illness including psychiatric illness, or situations that would limit compliance with the study requirements or the ability to willingly give written informed consent.

Contacts and Locations

Locations

United States, California

University of California San Francisco

San Francisco, California, United States, 94143

Sponsors and Collaborators

Jennifer Clarke

Investigators

• Principal Investigator: Jennifer Clarke, MD; University of California, San Francisco

More Information

• Responsible Party: Jennifer Clarke, Associate Professor, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT03681028
• Other Study ID Numbers: 18108; NCI-2018-02194 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
• First Posted: September 21, 2018
• Last Update Posted: May 3, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Jennifer Clarke, University of California, San Francisco:

Glioblastoma; Adult Glioblastoma; Glioma; Precision Medicine; Specialized Tumor Board

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue