Safety and Efficacy of NEO212 in Patients with Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype or Brain Metastasis
- Conditions
- Glioblastoma, IDH-wildtypeHead and Neck Squamous Cell CarcinomaMelanomaMerkel Cell CarcinomaMismatch Repair Deficient Solid Malignant TumorMicrosatellite Instability-High Colorectal CancerColorectal CancerMicrosatellite Instability-High Solid Malignant TumorNon-small Cell Lung CancerRenal Cell Carcinoma
- Interventions
- Drug: NEO212 Oral CapsuleDrug: FOLFIRI Protocol
- Registration Number
- NCT06047379
- Lead Sponsor
- Neonc Technologies, Inc.
- Brief 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.
- Detailed Description
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 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 brain metastasis. The study will have three phases, Phase 1, Phase 2a and Phase 2b.
Phase 1 is a standard cohort dose escalation 3+3 design with a modified Fibonacci dose escalation used to determine the maximum tolerated dose to select a recommended Phase 2 dose (RP2D) of NEO212 for Phase 2a and Phase 2b. The initial dose of NEO212 will be 170 mg and the dose will increase in successive cohorts (220, 400, 610, 810, and 1,000 mg) until a MTD is reached and a RP2D is selected. There will be up to 42 patients enrolled in Phase 1. In the event two DLTs are experienced in any cohort, a dose de- escalation cohort will be followed (with half of the dose increase from the previous cohort) to determine the MTD/RP2D.
Phase 2a is a safety run-in study with a standard 3+3 design used to confirm the safety of the MTD/RP2D of NEO212 when given in combination with select SOC regimens (as defined in Appendix 1) for patients with uncontrolled metastases to the brain (see Appendix 2). There will be up to 12 patients enrolled into each combination regimen to confirm safety. One dose below the NEO212 MTD/RP2D Cohort Dose will be administered as a starting dose to establish safety (3+3), before moving to Phase 2b with the MTD/RP2D (3+3). In the event that two DLTs are experienced for patients receiving the MTD/RP2D in combination with SOC, the dose de-escalation cohort will be expanded to determine the MTD for a newly established Phase 2b Treatment Group.
Phase 2b is a dose expansion study to assess efficacy of NEO212 alone, at the MTD/RP2D in patients with Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype as a single Treatment Group. A second Treatment Group to study the MTD/RP2D of NEO212 in combination with select SOC regimens in patients with solid tumors and uncontrolled metastases to the brain established in Phase 2a will be evaluated. Phase 2b will be initiated for patients with Astrocytoma IDH-mutant or Glioblastoma IDH-wildtype alongside Phase 2a. There will be up to 28 patients enrolled to have 27 evaluable patients enrolled in each Phase 2b Treatment Group.
For all phases of the study, NEO212 will be self-administered daily for days 1-5 of a 28- day treatment cycle.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 134
Not provided
(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).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 2a Safety Run-In - NEO212 and Nivolumab NEO212 Oral Capsule The following primary cancers with uncontrolled metrastases to the brain: * Unresectable or metastatic melanoma. * Metastatic non-small cell lung cancer. * Advanced renal cell carcinoma. * Squamous cell carcinoma of the head and neck. * Urothelial carcinoma. * Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. * Unresectable esophageal squamous cell carcinoma (ESCC). NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Nivolumab - 240 mg administered every 2 weeks per package insert Phase 2a Safety Run-In - NEO212 and Ipilimumab NEO212 Oral Capsule - Unresectable or metastatic melanoma with uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Ipilimumab - 3 mg/kg administered IV over 90 minutes every 3 weeks for a maximum of 3 doses per package insert. Phase 2a Safety Run-In - NEO212 and CarbolaUn (ParaplaUn) + Paclitaxel (Taxol) NEO212 Oral Capsule - Colorectal cancer (CRC) with uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Carboplatin - 300 mg/m2 IV on day 1 every 4 weeks for 6 cycles per package insert. Paclitaxel - 135mg/m2 IV administered over 24 hours, every 3 weeks per package insert. Phase 2a Safety Run-In - NEO212 and FOLFIRI (Zaltrap) + Bevacizumab (Avastin) FOLFIRI Protocol - Metastatic colorectal cancer (mCRC) with uncontrolled metastases to the brain, that is resistant to or has progressed following an oxaliplatin-containing regimen NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. FOLFIRI - 4 mg/kg aIV over 1 hour every 2 weeks. Bevacizumab - 10 mg/kg IV every 2 weeks. Phase 2b efficacy - NEO212 for Astrocytoma IDH-mutant and Glioblastoma IDH-wildtype NEO212 Oral Capsule Patients receiving NEO212 alone for treatment of Astrocytoma IDH-mutant and Glioblastoma IDH-wildtype. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Phase 2b efficacy - NEO212 & SOC for Uncontrolled Metastases to the Brain Nivolumab Patients receiving NEO212 in combination with select standard of care treatments for treatment of uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. SOC treatments established to be safe in Phase 2a of the study will be used in this arm of Phase 2b. Phase 2a Safety Run-In - NEO212 and Pembrolizumab NEO212 Oral Capsule The following primary cancers with uncontrolled metrastases to the brain: * Unresectable or metastatic melanoma. * NSCLC expressing PD-L1, with no EGFR or ALK genomic tumor aberrations. * Metastatic NSCLC whose tumors express PD-L1. * EGFR or ALK genomic tumor aberrations must have disease progression. * SCLC. * Unresectable, recurrent HNSCC whose tumors express PD-L1. * HNSCC on or after platinum-containing chemotherapy. * Urothelial carcinoma whose tumors express PD-L1. * Urothelial carcinoma. * Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). * Microsatellite Instability-high or Mismatch Repair Deficient Colorectal Cancer (CRC). * Gastric or gastroesophageal junction adenocarcinoma. * Esophageal or gastroesophageal juncUon (GEJ). * Cervical cancer. * Merkel cell carcinoma. NEO212 - Same as Arm 1. Pembrolizumab - 200 mg administered every 3 weeks per package insert. Phase 2a Safety Run-In - NEO212 and FOLFIRI (Zaltrap) + Bevacizumab (Avastin) NEO212 Oral Capsule - Metastatic colorectal cancer (mCRC) with uncontrolled metastases to the brain, that is resistant to or has progressed following an oxaliplatin-containing regimen NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. FOLFIRI - 4 mg/kg aIV over 1 hour every 2 weeks. Bevacizumab - 10 mg/kg IV every 2 weeks. Phase 2b efficacy - NEO212 & SOC for Uncontrolled Metastases to the Brain NEO212 Oral Capsule Patients receiving NEO212 in combination with select standard of care treatments for treatment of uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. SOC treatments established to be safe in Phase 2a of the study will be used in this arm of Phase 2b. Phase 2a Safety Run-In - NEO212 and Stivarga (Regorafenib) NEO212 Oral Capsule - Colorectal cancer (CRC) with uncontrolled metastases to the brain who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anU-EGFR therapy. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Stivarga - 160 mg orally, once daily for the first 21 days of each 28-day cycle per package insert Phase 2b efficacy - NEO212 & SOC for Uncontrolled Metastases to the Brain FOLFIRI Protocol Patients receiving NEO212 in combination with select standard of care treatments for treatment of uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. SOC treatments established to be safe in Phase 2a of the study will be used in this arm of Phase 2b. Phase 2b efficacy - NEO212 & SOC for Uncontrolled Metastases to the Brain Ipilimumab Patients receiving NEO212 in combination with select standard of care treatments for treatment of uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. SOC treatments established to be safe in Phase 2a of the study will be used in this arm of Phase 2b. Phase 2a Safety Run-In - NEO212 and Ipilimumab Ipilimumab - Unresectable or metastatic melanoma with uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Ipilimumab - 3 mg/kg administered IV over 90 minutes every 3 weeks for a maximum of 3 doses per package insert. Phase 2a Safety Run-In - NEO212 and Stivarga (Regorafenib) Regorafenib - Colorectal cancer (CRC) with uncontrolled metastases to the brain who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anU-EGFR therapy. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Stivarga - 160 mg orally, once daily for the first 21 days of each 28-day cycle per package insert Phase 2a Safety Run-In - NEO212 and Pembrolizumab Pembrolizumab The following primary cancers with uncontrolled metrastases to the brain: * Unresectable or metastatic melanoma. * NSCLC expressing PD-L1, with no EGFR or ALK genomic tumor aberrations. * Metastatic NSCLC whose tumors express PD-L1. * EGFR or ALK genomic tumor aberrations must have disease progression. * SCLC. * Unresectable, recurrent HNSCC whose tumors express PD-L1. * HNSCC on or after platinum-containing chemotherapy. * Urothelial carcinoma whose tumors express PD-L1. * Urothelial carcinoma. * Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). * Microsatellite Instability-high or Mismatch Repair Deficient Colorectal Cancer (CRC). * Gastric or gastroesophageal junction adenocarcinoma. * Esophageal or gastroesophageal juncUon (GEJ). * Cervical cancer. * Merkel cell carcinoma. NEO212 - Same as Arm 1. Pembrolizumab - 200 mg administered every 3 weeks per package insert. Phase 2a Safety Run-In - NEO212 and Nivolumab Nivolumab The following primary cancers with uncontrolled metrastases to the brain: * Unresectable or metastatic melanoma. * Metastatic non-small cell lung cancer. * Advanced renal cell carcinoma. * Squamous cell carcinoma of the head and neck. * Urothelial carcinoma. * Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. * Unresectable esophageal squamous cell carcinoma (ESCC). NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Nivolumab - 240 mg administered every 2 weeks per package insert Phase 2a Safety Run-In - NEO212 and CarbolaUn (ParaplaUn) + Paclitaxel (Taxol) Carboplatin - Colorectal cancer (CRC) with uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Carboplatin - 300 mg/m2 IV on day 1 every 4 weeks for 6 cycles per package insert. Paclitaxel - 135mg/m2 IV administered over 24 hours, every 3 weeks per package insert. Phase 2a Safety Run-In - NEO212 and CarbolaUn (ParaplaUn) + Paclitaxel (Taxol) Paclitaxel - Colorectal cancer (CRC) with uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. Carboplatin - 300 mg/m2 IV on day 1 every 4 weeks for 6 cycles per package insert. Paclitaxel - 135mg/m2 IV administered over 24 hours, every 3 weeks per package insert. Phase 2a Safety Run-In - NEO212 and FOLFIRI (Zaltrap) + Bevacizumab (Avastin) Bevacizumab - Metastatic colorectal cancer (mCRC) with uncontrolled metastases to the brain, that is resistant to or has progressed following an oxaliplatin-containing regimen NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. FOLFIRI - 4 mg/kg aIV over 1 hour every 2 weeks. Bevacizumab - 10 mg/kg IV every 2 weeks. Phase 2b efficacy - NEO212 & SOC for Uncontrolled Metastases to the Brain Pembrolizumab Patients receiving NEO212 in combination with select standard of care treatments for treatment of uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. SOC treatments established to be safe in Phase 2a of the study will be used in this arm of Phase 2b. Phase 2b efficacy - NEO212 & SOC for Uncontrolled Metastases to the Brain Paclitaxel Patients receiving NEO212 in combination with select standard of care treatments for treatment of uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. SOC treatments established to be safe in Phase 2a of the study will be used in this arm of Phase 2b. Phase 2b efficacy - NEO212 & SOC for Uncontrolled Metastases to the Brain Carboplatin Patients receiving NEO212 in combination with select standard of care treatments for treatment of uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. SOC treatments established to be safe in Phase 2a of the study will be used in this arm of Phase 2b. Phase 2b efficacy - NEO212 & SOC for Uncontrolled Metastases to the Brain Regorafenib Patients receiving NEO212 in combination with select standard of care treatments for treatment of uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. SOC treatments established to be safe in Phase 2a of the study will be used in this arm of Phase 2b. Phase 2b efficacy - NEO212 & SOC for Uncontrolled Metastases to the Brain Bevacizumab Patients receiving NEO212 in combination with select standard of care treatments for treatment of uncontrolled metastases to the brain. NEO212 - Starting one dose level under RP2D administered orally on days 1 - 5 of a 28-day treatment cycle, escalated to RP2D per Protocol dose escalation rules. SOC treatments established to be safe in Phase 2a of the study will be used in this arm of Phase 2b.
- Primary Outcome Measures
Name Time Method Phase 1: safety and tolerability of increasing dose levels of orally administered NEO212 alone in patients with Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype or patients with select solid tumors with uncontrolled metastases to the brain 6 months As determined by incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0
Phase 1: Identify the maximum tolerated dose (MTD) of NEO212 6 months Maximum Tolerated Dose of NEO212 as determined by the dose escalation rules.
Phase 1: Determine the recommended Phase 2 dose (RP2D) of NEO212 6 months Determine the recommended Phase 2 dose (RP2D) of NEO212
Phase 2a: Assess the safety and tolerability of orally administered NEO212 in combination with select SOC regimens following a standard 3+3 design in patients with select solid tumors with uncontrolled metastases to the brain 6 months Determined by incidence and severity of adverse events determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0).
Phase 2b: Determine the intracranial progression-free survival rate at six months (PFS6) of orally administered NEO212 alone in patients with Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype. 6 months Determine the intracranial progression-free survival rate at six months (PFS6) of orally administered NEO212 alone in patients with Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype.
Phase 2b: Determine the intracranial progression-free survival rate at six months (PFS6) of orally administered NEO212 in combination with select SOC regimens in patients with select solid tumors with uncontrolled metastases to the brain. 6 months Determine the intracranial progression-free survival rate at six months (PFS6) of orally administered NEO212 in combination with select SOC regimens in patients with select solid tumors (see Appendix 2) with uncontrolled metastases to the brain.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (2)
Precision NextGen Oncology
🇺🇸Beverly Hills, California, United States
Northwest Medical Specialties
🇺🇸Tacoma, Washington, United States