PRP Phase 1b FIH: Novel Mechanism Enters Clinic With No Human Data, No Disclosed Target

Propanc Biopharma Plans World-First Phase 1b FIH Study of PRP

Propanc Biopharma announced plans to initiate a world-first Phase 1b first-in-human (FIH) study of its lead product candidate, PRP, in February 2027. This multicenter, open-label, two-part study will enroll up to 50 patients with advanced solid tumors, including pancreatic, ovarian, and refractory prostate cancers, across Australia. The study aims to evaluate PRP's safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity, with weekly intravenous infusions.

• The Phase 1b FIH study of PRP is an open-label, two-part dose-escalation (Part A) and dose-expansion (Part B) trial. It will enroll up to 50 patients suffering from advanced solid tumors, specifically pancreatic, ovarian, and refractory prostate cancers, at various trial centers throughout Australia.
• PRP will be administered as a weekly intravenous infusion on Days 1, 8, 15, and 22 of each 28-day cycle. The primary objectives include assessing the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PRP, alongside evaluating its preliminary antitumor activity in the target patient population.
• Propanc Biopharma is actively progressing key workstreams to support the study's February 2027 start. This includes ongoing GMP manufacturing of the finished drug product, commencement of PK method validation and anti-drug antibody assay development, and preparation of regulatory documentation for Human Research Ethics Committee (HREC) submission planned for November 2026.

PRP's Novel Proenzyme Activation for Advanced Solid Tumors

Recent oncology research has identified several novel cell-surface and molecular targets with potential therapeutic relevance across advanced solid tumors. B7-H3 (CD276) has emerged as a particularly compelling antibody-drug conjugate (ADC) target, with membranous expression detected in 91% of medullary thyroid carcinoma (MTC) cases — including strong expression in 82% — consistent across tumor stages and clinical subgroups. In contrast, Nectin-4, Trop-2, c-Met, PD-L2, and Claudin 18.2 showed no expression in evaluable MTC samples, underscoring the limited landscape of actionable surface antigens in this disease. More broadly, ADC development is increasingly oriented toward histology-agnostic expansion, with targets such as Trop-2, nectin-4, and HER2 demonstrating activity across multiple tumor types including breast, gastric, colorectal, and lung cancer. Claudin 18.2 and B7-H3 have also been highlighted as novel targets under active investigation in CAR-T cell therapy for solid tumors.

At the molecular level, KRAS G12D has attracted significant research attention as a driver mutation targetable across multiple solid tumor histologies. A novel KRAS G12D inhibitor, compound 16k, built on a 6-methoxyquinazoline scaffold, exhibited antiproliferative activity against KRAS G12D mutant tumor cell lines AGS and GP2D with IC values of 0.18 and 0.21 μM, respectively, while demonstrating minimal cytotoxicity toward normal cells. Separately, high-dose L-ascorbic acid (AA) indicated selective inhibition of KRAS G12D-mutant pancreatic cancer cell growth through glycolysis inhibition via GAPDH inactivation and DNA damage induction, with synergistic activity observed in combination with the DNA-damaging agent AZD6738. In advanced biliary tract cancer (BTC), cfDNA profiling of 1,671 patients identified targetable alterations in 44% of cases, with KRAS G12C (1.0%), KRAS G12D (5.1%), PIK3CA mutations (6.8%), and ERBB2 amplifications (4.9%) among the promising targets currently under investigation.

Beyond mutation-directed strategies, metabolic and immune-oncology targets are also under active exploration. AZD3965, a first-in-class oral monocarboxylate transporter 1 (MCT1) inhibitor, demonstrated on-target pharmacodynamic activity in a phase I dose-escalation trial enrolling patients with advanced solid tumors or lymphoma, with a recommended phase II dose (RP2D) of 10 mg twice daily established for cancers expressing high MCT1/low MCT4. In the RET-altered space, the selective RET inhibitor SY-5007 achieved an overall objective response rate (ORR) of 57.8% across 116 efficacy-evaluable patients with RET-altered solid tumors, including non-small cell lung cancer, medullary thyroid cancer, papillary thyroid cancer, and gastric cancer, with a median progression-free survival (PFS) of 21.1 months. Resistance mechanisms in relapsed patients were predominantly off-target, identified in 57.1% (12/21) of cases, with no on-target RET alterations detected.

Designing Propanc's First-in-Human Phase 1b Study of PRP

Several key clinical trials in advanced solid tumors span a range of therapeutic modalities — from targeted agents and immunotherapy combinations to radiosurgery and viral immunotherapy — each employing distinct design parameters and endpoint frameworks.

Addressing Unmet Needs in Advanced Solid Tumor Treatment

The treatment of advanced solid tumors remains one of oncology's most formidable challenges, shaped by the biological complexity of tumors and the limitations of available therapeutic modalities. Despite meaningful advances across targeted therapy, immunotherapy, and cellular approaches, durable responses remain elusive for a substantial proportion of patients.

• Emergence of drug resistance to targeted therapies: Therapeutic responses to kinase-targeted small molecule therapies are often of limited duration, typically 6–12 months, because of the emergence of drug-resistant subclones of tumor cells. Mechanisms driving this resistance include gene amplification, overexpression, autocrine activation, and crosstalk with other signaling pathways — with MET identified as a well-known driver of acquired resistance to several classes of targeted therapies.

• Immunosuppressive tumor microenvironment (TME): CAR-T cell therapy's efficacy in solid tumors remains limited due to antigen heterogeneity, a suppressive tumor microenvironment, and tumor-intrinsic resistance mechanisms. Similarly, immune checkpoint blockade therapies often fail due to impaired antigen presentation, interferon signaling dysregulation, and immune exclusion. In clear cell renal cell carcinoma specifically, many tumors exhibit an "immune-cold" tumor immunosuppressive microenvironment characterized by poor T cell infiltration and multiple immunosuppressive barriers, leading to primary or acquired resistance to immune checkpoint inhibitors.

• T-cell exhaustion and immune evasion in neoadjuvant settings: Challenges in neoadjuvant immunotherapy persist due to the complexity of the TME, immune evasion, T-cell exhaustion, and the identification of reliable biomarkers — all of which are critical barriers to optimizing treatment regimens and minimizing immune-related adverse events.

• Biomarker identification and equitable patient selection: Predictive biomarker testing is necessary to determine the presence of oncogenic alterations in order to select patients most likely to respond and to avoid the use of ineffective and potentially harmful alternative therapy. Barriers and disparities in biomarker testing remain a concern, with advanced practitioners needing to address these gaps to ensure equitable care for all patients.

• Toxicity and trial discontinuation in combination regimens: Combination approaches carry significant safety challenges. In the CEP-9722 study evaluating a PARP-1 and PARP-2 inhibitor combined with gemcitabine and cisplatin, the study was discontinued before determination of the maximum-tolerated dose because of highly variable CEP-8983 exposure in all cohorts and toxicity, particularly chemotherapy-induced myelosuppression, with adverse events leading to discontinuation in 33% of patients.

• Overexpression of anti-apoptotic proteins driving intrinsic and acquired resistance: Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies, underscoring the role of apoptotic pathway dysregulation as a persistent barrier to treatment efficacy across hematological and solid tumor settings.

Pioneering Pancreatic Enzyme Therapy for Advanced Cancers

The upcoming initiation of a world-first Phase 1b first-in-human study for PRP represents a pivotal moment for a novel therapeutic strategy in oncology. This investigational product, a unique formulation of pancreatic pro-enzymes trypsinogen and chymotrypsinogen A, is poised to explore a multi-modal approach to combating advanced solid tumors, including pancreatic, ovarian, and refractory prostate cancers—indications notorious for their aggressive nature and limited treatment options.

Research has consistently highlighted the diverse anti-tumor capabilities of PRP. Studies indicate its ability to exert synergistic anti-tumor effects, inhibit angiogenesis, and reduce cancer cell migration and invasiveness. Furthermore, there's compelling evidence that PRP can sensitize Cancer Stem Cells (CSCs), a critical factor in tumor recurrence and resistance. More recently, the scientific community has turned its attention to trypsinogen's potential as an immunomodulator, with findings suggesting it can reprogram tumor-associated macrophages (TAMs) to a more anti-tumorigenic phenotype. This opens exciting avenues for PRP, not just as a standalone therapy, but potentially in combination with existing immunotherapies, offering a fresh perspective on tackling the immunosuppressive tumor microenvironment.

However, as with any pioneering therapy, there are important considerations. The transition from preclinical models and early compassionate use (with a suppository formulation) to an intravenous Phase 1b study introduces new safety parameters. Given the known role of trypsinogen in pancreatitis, careful monitoring for systemic adverse events will be paramount. The challenge also lies in translating the observed preclinical efficacy into a robust clinical benefit across a broader patient population. While the mechanism is novel, the competitive landscape for advanced cancers demands that PRP demonstrate a clear and significant advantage to secure its place in future treatment paradigms. This study, therefore, is not just about safety and preliminary efficacy; it's about validating a new class of agents that could fundamentally reshape how we approach some of the most intractable cancers.