GO‑4 Drug Combo Offers New Hope for Treating Late-Stage BRCA/PALB2-Mutated Cancers

By Ray Dogum, Chief Editor, Drug Discovery Online

General Oncology’s GO‑4 is an investigational combination product designed to shut down DNA repair and resensitize hard‑to‑treat tumors to chemotherapy using what the company calls Advanced Redox Modulation. The regimen, for patients with advanced pancreatic or breast cancer, combines melphalan, BCNU, hydroxocobalamin, and ascorbic acid with an autologous stem cell rescue delivered in two cycles roughly six weeks apart.

Early Phase 1 data presented on the SHARON trial reported a manageable safety profile and a strong efficacy signal, including two stage IV pancreatic cancer patients progression‑free at ~4 years and ~2 years after only two cycles and no further therapy. The preliminary dataset included eleven patients with metastatic pancreatic ductal adenocarcinoma and one with breast cancer.

I spoke with Jeff Glazier, General Oncology’s CEO, about the scientific rationale, the decision to pursue a multi‑drug regimen, how their lead candidate GO‑4 may differ from maintenance PARP inhibition, and what’s next for the company.

“It was born out of necessity.”

Jeff traces the company’s combination approach to a family crisis and a constraint that forced creativity. His aunt Sharon was diagnosed with pancreatic cancer in 2012. As he told me:

“When [my aunt] had her surgical resection at Mass General, they found that it had spread to 6 of the 17 resected nodes, and one of them was a common hepatic artery node, which is almost universally fatal. There was really no point to going through traditional chemotherapy, and there wasn’t time to develop a new drug," recalls Glazier. Meanwhile, Glazier's uncle (and sister to the patient), Arnold Glazier, M.D., found himself working round the clock to determine a course of treatment using available drugs.  

From that inflection point, Jeff and Arnold, who now serves General Oncology as Chief Scientific Officer, assembled a regimen using already approved agents to target tumor biology differently when combined. The mechanistic logic: hydroxocobalamin and ascorbic acid drive redox shifts (increasing dehydroascorbic acid and hydrogen peroxide uptake by tumor cells) that deplete glutathione and impair DNA repair, while BCNU blocks the enzyme that would restore the reduced state. The net effect is to hypersensitize tumor DNA to melphalan cross‑linking.

Two-Cycles And Done

What makes GO‑4 stand out, Glazier argues, is not just its components but the treatment cadence. “In our trial, patients receive 2 cycles approximately 6 weeks apart, and then they receive no further treatment,” he says.

That’s different from maintenance PARP inhibitor strategies (e.g., olaparib) used on first‑line chemotherapy in BRCA‑mutated pancreatic cancer, where patients continue daily dosing. In AstraZeneca’s POLO trial, median progression‑free survival (PFS) with olaparib was 7.4 months among eligible patients. General Oncology’s data indicates that among SHARON patients with stable or responding disease at enrollment, median PFS was almost double at 14.2 months, with no maintenance therapy after two cycles, and no treatment‑related mortality or long‑term toxicities reported in the safety‑focused Phase 1.

Autologous Stem Cell Support

Because melphalan can be myelosuppressive, GO‑4 includes pre‑collection and reinfusion of the patient’s own hematopoietic stem cells.

“Melphalan is what’s called myelosuppressive, so we collect the patient’s bone marrow stem cells in advance, through apheresis. We freeze the stem cells, which is done all the time for cancers like myeloma,” says Glazier

This combination‑plus‑support design is central to how General Oncology frames GO‑4. It’s not just four drugs, but a procedural regimen intended to hit tumors from multiple angles while limiting side effects.

From Stage IV Proof Of Concept To Earlier‑Stage Ambition

Why start in Stage IV pancreatic ductal adenocarcinoma (PDAC) and then expand? Glazier’s answer was pragmatic and anchored in signal detection:

“We would love to use this, not just for Stage IV cancer, but for the earlier stages, too. When you get results like this, which are unheard of in the industry, it’s a bigger splash. Once you’re at Stage IV, the median PFS is so low that having something like this, it’s an unheard‑of number.”

The SHARON enrolled metastatic PDAC and one breast cancer patient, initially with inherited BRCA/PALB2 mutations. Future enrollment opened to patients with or without such mutations. This hints at a broader hypothesis: if Advanced Redox Modulation suppresses DNA repair broadly, benefit might not be limited to homologous recombination–deficient tumors.

Pipeline Breadth: More Shots On Goal

Beyond GO‑4, General Oncology is advancing distinct programs, including a small‑molecule candidate (internally referenced as JG‑1) that halts cell proliferation without cell death, with potential applications in oncology and ophthalmology (e.g., wet AMD and diabetic retinopathy).

“We actually have some really exciting stuff for ophthalmology. We designed a drug that shuts down cell proliferation without killing the cells. In a pilot rabbit study, that drug worked phenomenally well.” Glazier says General Oncology has another treatment in development for prostate cancer.

Fundraising And The Near‑term Plan

With their Phase 1 expansion trial underway to refine dosing, Glazier says it hasn’t yet hit a maximum tolerated dose, so there is potential for greater efficacy with their treatment.

Glazier described the financing climate as improving given their dataset to date. “The general feedback we get is that people haven’t seen data like this before. The market’s coming back, and there’s interest.”

While combination regimens are hardly new in oncology, mechanism‑layered combinations that minimize long‑term toxicity remain a frontier. General Oncology’s early Phase 1 signals are encouraging, and the next phase will need to show consistency, safety at optimized doses, and comparative benefit versus current standards in appropriate patient subsets.

If those data hold up, GO‑4 could reframe how we think about combination products in solid tumors.

About Jeff Glazier, J.D.

A founding member of General Oncology, Jeff has been Chief Executive Officer since August 2024 and was previously Chief Operating Officer since 2019. In both roles, he has been responsible for all business decisions of General Oncology. He determined corporate strategy, vetted and selected clinical trial sites, managed all non-medical aspects of the SHARON Trial, selected laboratories for preclinical work, carried out all clinical trial tasks that would typically be performed by a contract research organization other than medical monitoring and clinical data monitoring, performed the function of an in-house legal counsel for all corporate and research matters, selected and maintained the IT infrastructure, and played a pivotal role in securing the company’s patents. Prior to General Oncology, he was a co-founder of the health-care technology company ProviderTech LLC and a private equity attorney at Ropes & Gray LLP. He holds a J.D. from Harvard Law School and an Sc.B. in neuroscience from Brown University.

About General Oncology, Inc.

General Oncology is a clinical-stage biopharmaceutical company dedicated to pioneering first-in-class medicines for metastatic cancers and other proliferative diseases. The Company is developing GO-4, an investigational therapy for metastatic cancers, currently completing the Phase 1 SHARON trial (NCT04150042) for metastatic cancers in the setting of a BRCA1/2 or PALB2 mutation. With a commitment to innovation, General Oncology is focused on advancing transformative therapies for cancer patients. For more information about General Oncology, please visit www.generaloncology.com