Safety and Efficacy of NEO212 in Patients With Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype or Brain Metastasis

Summary

This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 alone for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH- mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled metastases to the brain. The study will have three phases, Phase 1, Phase 2a and Phase 2b.

Interventions

• NEO212 Oral Capsule · DRUG

  NEO212 is a novel chemical entity that was generated by covalent conjugation of temozolomide (TMZ) with perillyl alcohol (POH).

• Ipilimumab · DRUG

  Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system. Cytotoxic T lymphocytes can recognize and destroy cancer cells.

• Pembrolizumab · DRUG

  Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is given by slow injection into a vein.

• Nivolumab · DRUG

  Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer.

• Regorafenib · DRUG

  Regorafenib, sold under the brand name Stivarga among others, is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase. Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition

• Carboplatin · DRUG

  Carboplatin, sold under the trade name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is used by injection into a vein.

• Paclitaxel · DRUG

  Paclitaxel, sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered by intravenous injection

• FOLFIRI Protocol · DRUG

  FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer. It is made up of the following drugs: FOL - folinic acid (leucovorin), a vitamin B derivative with multiple applications, which in this context increases the cytotoxicity of 5-fluorouracil; F - fluorouracil (5-FU), a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops synthesis; and IRI - irinotecan (Camptosar), a topoisomerase inhibitor, which prevents DNA from uncoiling and duplicating.

• Bevacizumab · DRUG

  Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein and used for colon cancer, lung cancer, glioblastoma, and renal-cell carcinoma

Published eligibility criteria

Verbatim from the registry. Only the site can decide how these apply to a specific patient.

Inclusion Criteria:

* Patient must be ≥ 18yrs of age.
* Patient must have the ability to understand, and the willingness to sign, a written informed consent form.
* Patient has been on a stable or decreasing dose of steroids for at least five days prior to the date of informed consent.
* Any toxicity from prior therapy must be resolved or at maximum Grade 1 prior to initiation of NEO212.
* If progression of disease occurs within 90 days or conformal radiation, the progression/recurrence must be outside of the radiation field or proven by biopsy/resection.
* Patient with Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype must have a Karnofsky Performance Status (KPS) of ≥ 60.
* Patient with select solid tumors must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
* Patient must have an expected survival or at least three months.
* Patient must have a baseline MRI of the brain with gadolinium within 14 days of administration of NEO212.
* Patient with select solid tumors must have a baseline CT scan with IV contrast and oral contrast of neck, chest, abdomen and pelvis within 14 days of administration of NEO212.
* Patients must be able to comply with all study assessments.
* If patient suffers from seizures (s)he must be controlled on a stable dose of anti-epileptics for 14-days prior to the date of informed consent.
* Patient must have adequate organ and marrow function as follows:

  * Absolute neutrophil count ≥ 1,500/microliter
  * Platelets ≥ 100,000/microliter
  * Total bilirubin within normal institutional limits
  * AST (SGOT) / ALT (SPGT) ≤ 2.5 x institutional upper limit of normal
  * Creatinine clearance (CrCl) of \>60 mL/min (using the Cockcroft-Gault formula or 24- hour urine collection).
* Female patients of child-bearing potential and male patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for 30 days prior to the first dose of NEO212, for the duration of study participation, and for 90 days following completion of therapy.

A female of child-bearing potential is any women (regardless of sexual orientation, not having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

* Has not undergone a hysterectomy or bilateral oophorectomy; or
* Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has not had menses at any time in the preceding 12 consecutive months).
* A negative serum pregnancy test will be required of all female patients of child-bearing potential within seven days prior to the receipt of NEO212.
* A serum pregnancy test will be repeated immediately if pregnancy is suspected.

Phase 1: (dose escalation)

* Patient must:

  * have radiographically confirmed Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype following previous radiation therapy or treatment with temozolomide and radiation, or
  * have select solid tumors with uncontrolled metastases to the brain (confirmed by cranial CT or MRI) that is not controlled by surgery or radiation therapy and receiving one of the protocol approved SOC regimens.
* Patients receiving prior systemic therapy must have a minimum wash-out period (defined as the period prior to receipt of the first dose of NEO212) of:

  * 28 days or 5 half-lives (whichever is shorter) elapsed from the administration from any experimental agent;
  * 2 weeks from administration of immunotherapies;
  * 28 days from administration of cytotoxic agents; and
  * 7 days from administration of non-cytotoxic agents (interferon, tamoxifen, thalidomide, cis-retinoic acid, and herbal medicine).

NOTE: No washout is necessary for alternating electrical fields.

Phase 2a: (safety run-in)

* Patient must have select solid tumors with uncontrolled metastases to the brain (confirmed by cranial CT or MRI) that is not controlled by surgery or radiation therapy and receiving one of the protocol approved SOC regimens.
* Patients receiving prior systemic therapy must be receiving one of the protocol approved Standard of Care (SOC) regimens.
* Patient must have measurable/evaluable CNS disease per RANO or RANO-BM criteria.
* Patient must have measurable/evaluable systemic disease per RECIST v1.1 criteria.

Phase 2b: (efficacy)

* Patient must:

  * have radiographically confirmed Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype following previous radiation therapy or treatment with temozolomide and radiation, or
  * have select solid tumors with uncontrolled metastases to the brain (confirmed by cranial CT or MRI) that is not controlled by surgery or radiation therapy and receiving one of the protocol approved SOC regimens.
* Patients receiving prior systemic therapy must be receiving one of the protocol approved Standard of Care (SOC) regimens.
* Patient must have measurable/evaluable CNS disease per RANO or RANO-BM criteria
* Patient with select solid tumors must have measurable/evaluable systemic disease per RECIST v1.1 criteria.
* Creatinine clearance (CrCl) of \>60 mL/min (using the Cockcroft-Gault formula or 24-hour urine collection). Female patients of child-bearing potential and male patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for 30 days prior to the first dose of NEO212, for the duration of study participation, and for 90 days following completion of therapy.

Exclusion Criteria: (all Phases)

* Patient in Phase 1 concurrently receiving any other antitumor therapy.
* Patient in Phase 2a or 2b who is concurrently receiving any SOC therapy not listed in Appendix 1.
* Patients with metastases to the spinal cord parenchyma.
* Patients with metastases to the meninges.
* Patient has received stereotactic or highly conformal radiotherapy to CNS lesions within 2 weeks before receipt of NEO212.
* Patient with history of known leptomeningeal involvement.
* Patient has prior history or new diagnosis of secondary cancer within five years prior to the date of informed consent, except for basal cell carcinoma or squamous cell carcinoma of the skin.
* Patient has a corrected QT interval (using Fridericia's correction formula) (QTcF) of \>470 msec, a history of additional risk factors for TdP (e.g. heart failure, hypokalemia), and/or the use of concomitant medications that prolong QT/QTc interval.
* Patient had surgery within 7 days prior to the date of informed consent.
* Patient has not recovered to Grade 1 from treatment related adverse events due to chemotherapy, immunotherapy, or radiation therapy.
* Patient had prior treatment with perillyl alcohol.
* Patient has a history of allergic reactions attributed to perillyl alcohol.
* Patients in Phase 2b with Astrocytoma IDH-mutant, or Glioblastoma IDH-wildtype who have had more than one recurrence or progression of his/her primary CNS tumor(s).

Sites (7)

• Precision NextGen Oncology, Beverly Hills, California · RECRUITING
• OPN Healthcare, Inc, Glendale, California · RECRUITING
• University of Southern California, Los Angeles, California · RECRUITING
• MDR Core Network, Boynton Beach, Florida · RECRUITING
• Vanderbilt University Medical Center, Nashville, Tennessee · RECRUITING
• Baylor, Scott and White Research Institute, Dallas, Texas · RECRUITING
• Northwest Medical Specialties, Tacoma, Washington · RECRUITING