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.

This is a single arm, non-randomized open-label study to assess feasibility of implementing an individualized treatment regimen in patients with surgical recurrent glioblastoma (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. The investigators 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.

Patients may continue treatment until tumor progression, intolerable side effects, or patient/physician choice to discontinue.

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.
8. Any other acute or chronic medical or psychiatric condition, or laboratory abnormality that could increase the risk associated with trial participation or trial drug administration or could interfere with the interpretation of trial results, and, in the judgment of the investigator, would make the patient inappropriate for entry into the trial.

De-identified data may be shared with study collaborators during the course of the study.