GZ17-6.02: An Investigational Multi-Component Oral Therapeutic for Cancer

1. Executive Summary

GZ17-6.02 is an orally administered, multi-component investigational therapeutic agent under development by Genzada Pharmaceuticals USA Inc. for the treatment of various malignancies.[1] While its conceptual origins may be linked to traditional botanical medicine, the formulation currently under clinical investigation is consistently described in recent scientific literature as a synthetic mixture of isovanillin (77% by mass), harmine (13%), and curcumin (10%).[4] This specific combination appears to exhibit unique biological properties distinct from its individual constituents.[5]

The proposed mechanism of action for GZ17-6.02 is multi-factorial, differentiating it from many targeted therapies. Key mechanisms include the inhibition of super-enhancers (SEs), critical transcriptional regulatory elements often dysregulated in cancer, leading to the downregulation of oncogenes.[7] Additionally, GZ17-6.02 initiates a DNA damage response, primarily through the activation of the ATM kinase pathway.[10] This activation triggers downstream signaling cascades involving AMPK activation, mTOR inhibition, and the induction of pronounced macroautophagy.[4] Notably, this induced autophagy appears essential for GZ17-6.02's cytotoxic effects in several cancer models.[4] The compound also modulates endoplasmic reticulum (ER) stress pathways, evidenced by PERK activation and eIF2α phosphorylation.[4] In certain contexts, particularly multiple myeloma, GZ17-6.02 promotes the autophagy-dependent degradation of histone deacetylases (HDACs) 1, 2, and 3.[4]

Extensive preclinical studies have demonstrated broad anti-tumor activity for GZ17-6.02 across a wide range of solid tumor and hematologic malignancy models, including pancreatic, colorectal, prostate, breast, lung, melanoma, glioblastoma, sarcoma, multiple myeloma, and mycosis fungoides.[4] Significant activity has been observed both as monotherapy and, perhaps more importantly, in synergistic or additive combinations with various standard-of-care agents, including chemotherapy (e.g., 5-FU, capecitabine, doxorubicin, pemetrexed), targeted therapies (e.g., proteasome inhibitors, PARP inhibitors, BRAF/MEK inhibitors, CDK4/6 inhibitors), and immunotherapy (anti-PD1).[2]

Clinically, GZ17-6.02 completed a Phase 1 dose-escalation trial (NCT03775525) in patients with advanced solid tumors and lymphoma.[4] This study established the Recommended Phase 2 Dose (RP2D) as 375 mg administered orally twice daily (PO BID) and demonstrated a manageable safety profile, characterized primarily by reversible Grade 1-3 liver enzyme elevations.[4] Preliminary efficacy signals were observed, including a partial response (PR) in c-MET amplified non-small cell lung cancer (NSCLC), tumor shrinkage in HER2 mutant NSCLC, and prolonged stable disease (SD) in several tumor types, including uveal melanoma.[16] Following the Phase 1 study, a Phase 1B trial combining GZ17-6.02 with capecitabine in metastatic breast cancer was initiated in May 2022.[2] Furthermore, a Phase 1 trial evaluating GZ17-6.02 monotherapy in patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) (NCT06636123/NCI-2024-09343) was planned to start in late 2024/early 2025.[1] GZ17-6.02 represents a novel, multi-targeted oral agent with significant preclinical activity and emerging clinical data supporting its further development, particularly in combination regimens.

2. Introduction

GZ17-6.02 is a novel, orally administered investigational compound being developed by Genzada Pharmaceuticals USA Inc., identified as a subsidiary of Ionics Pharmaceuticals SA or Ionics Life Sciences Limited.[2] The compound is currently advancing through early-phase clinical trials for the treatment of various cancers.[1]

The development of GZ17-6.02 appears to have origins linked to traditional Middle Eastern medicine, with early reports mentioning its derivation in part from the black calla lily (Arum palaestinum).[2] This plant has a history of use in herbal remedies.[3] However, the compound currently under clinical investigation is consistently described in recent scientific literature and patent documents as a specific, synthetically manufactured formulation containing three distinct components: isovanillin, harmine, and curcumin.[4] This synthetic, multi-component nature is a defining characteristic of GZ17-6.02.

GZ17-6.02 is positioned as a potential anti-cancer therapeutic with a unique, multi-faceted mechanism of action, differentiating it from single-target agents. Preclinical evidence suggests activity across a broad spectrum of malignancies, both as a single agent and, significantly, in combination with existing cancer therapies.[2] A Phase 1 clinical trial has established a recommended dose and schedule for further studies.[4]

This report aims to provide a comprehensive analysis of GZ17-6.02 based on the available research data. It will detail the compound's composition, elucidate its complex mechanism of action, summarize the extensive preclinical findings, and review the status and results of its clinical development program.

3. Composition and Formulation

The precise composition of GZ17-6.02 has been described differently across various sources, reflecting potential evolution in its development or variations in descriptive detail. However, the most consistent and recent scientific descriptions point to a specific synthetic formulation.

3.1. Reported Composition and Formulation

Recent peer-reviewed publications (dating from 2022 to 2024) and patent literature consistently describe GZ17-6.02 as a synthetically manufactured compound comprising three specific components by mass: isovanillin (77%), harmine (13%), and curcumin (10%).[4] A patent example (US20170105976A1) provides further detail on one method of preparation, combining solid synthetic isovanillin (specified as 98% purity), synthetic harmine (99% purity), and a commercially available curcumin product derived from turmeric (99.76% purity).[30] GZ17-6.02 is formulated for oral (PO) administration.[1] The Recommended Phase 2 Dose (RP2D) established from the Phase 1 trial (NCT03775525) is 375 mg administered orally twice daily (PO BID).[4]

3.2. Alternative Descriptions and Discrepancy

Contrasting descriptions exist, primarily in earlier documents or non-peer-reviewed sources. The NCI Drug Dictionary defines GZ17-6.02 as a "synthetic formulation of the Arum palaestinum plant... fortified with... isovanillin, linolenic acid, and beta-sitosterol".[8] Early press releases (2018-2019) describe it as "derived in part from the black calla lily (Arum palaestinum)" but also refer to it being composed of "three active pharmaceutical ingredients".[3]

The significant body of recent, detailed scientific literature consistently reporting the isovanillin/harmine/curcumin composition strongly suggests this is the formulation currently under clinical investigation. The alternative descriptions may represent earlier formulations, simplified explanations for broader communication, or potentially inaccurate database entries. The mention of Arum palaestinum likely refers to the plant source of harmine, one of the components, rather than the entire formulation being a direct plant extract.[5] This report focuses on the isovanillin/harmine/curcumin composition as defined in the predominant scientific evidence.

3.3. Component Properties and Synergy

While GZ17-6.02 functions as a distinct entity, understanding the properties of its individual components provides context:

• Isovanillin: An isomer of vanillin, known to inhibit aldehyde oxidase and xanthine oxidase. It possesses hydrogen bonding capabilities and is thought to complex with the other components, potentially contributing to the unique biological activity of the mixture.[5]
• Harmine: A beta-carboline alkaloid originally isolated from plants like Peganum harmala and Arum palaestinum. Preclinical studies suggest it may selectively affect tumor cells, potentially through DNA damage induction or inhibition of drug efflux pumps.[5]
• Curcumin: The primary active compound in turmeric, extensively studied for its broad anti-tumor activities, including modulation of PI3K/AKT/mTOR and EGFR signaling. However, curcumin alone suffers from poor solubility and bioavailability, limiting its clinical utility as a single agent.[5]

Crucially, preclinical studies emphasize that the combination of all three synthetic components in GZ17-6.02 results in significantly greater anti-tumor efficacy compared to the individual agents or dual combinations, suggesting a synergistic interaction that defines the drug's unique biological profile.[5] Isovanillin, in particular, is hypothesized to potentiate the activity of curcumin and harmine by forming a complex, leading to distinct biological properties.[7]

Table 1: GZ17-6.02 Composition Summary

Component	Chemical Class	Reported % by Mass	Source (Plant/Synthetic)	Key Individual Properties (Brief)	Source Snippet(s)
Isovanillin	Phenolic aldehyde	77%	Synthetic	Aldehyde oxidase/xanthine oxidase inhibitor; hydrogen bonding capability; complexes with other components	4
Harmine	Beta-carboline alkaloid	13%	Synthetic	Derived from medicinal plants; potential DNA damage; possible drug efflux pump inhibition	4
Curcumin	Polyphenol (Curcuminoid)	10%	Synthetic (from Turmeric)	Broad anti-tumor activity (e.g., PI3K/AKT/mTOR, EGFR pathways); poor solubility/bioavailability alone	4
Alternative
Linolenic acid	Fatty Acid	Not specified	Synthetic/Fortified	Component mentioned in NCI Drug Dictionary description	8
Beta-sitosterol	Phytosterol	Not specified	Synthetic/Fortified	Component mentioned in NCI Drug Dictionary description	8

4. Mechanism of Action (MOA)

GZ17-6.02 exerts its anti-cancer effects through a complex and multi-faceted mechanism of action, impacting several critical cellular pathways rather than relying on a single molecular target. This pleiotropic activity likely contributes to its broad preclinical efficacy and potential to overcome resistance mechanisms. Key components of its MOA identified in the provided sources include super-enhancer inhibition, induction of DNA damage response, modulation of autophagy and ER stress, and alteration of key signaling pathways.

4.1. Super-Enhancer Inhibition

A novel aspect of GZ17-6.02's proposed MOA is its ability to function as a super-enhancer (SE) inhibitor.[2] SEs are large clusters of transcriptional enhancers that drive high-level expression of genes crucial for cell identity and function. In cancer, SEs are often reprogrammed to drive the expression of key oncogenes, contributing to tumor growth, survival, and stemness.[36] Preclinical studies using RNA-Seq and ChIP-Seq assays demonstrated that GZ17-6.02 treatment disrupts SE networks in pancreatic cancer cells and glioblastoma stem cells (GSCs).[7] This disruption leads to changes in the expression of SE-associated genes. For instance, in GSCs, GZ17-6.02 downregulated the expression of specific glioblastoma SE genes (WSCD1, EVOL2, KLHDC8A) and FADS2, potentially impacting EGFR signaling and fatty acid metabolism pathways crucial for GSC survival.[7] The effect on SEs appeared more pronounced in cancer cells compared to cancer-associated fibroblasts (CAFs), suggesting a degree of tumor cell specificity in this mechanism.[9] Targeting SEs represents a distinct approach to disrupting the transcriptional programs that maintain the malignant state.

4.2. DNA Damage Response and ATM Activation

A consistent finding across multiple studies is that GZ17-6.02 treatment initiates a DNA damage response.[10] This is evidenced by the activation of the serine/threonine kinase ATM (Ataxia-Telangiectasia Mutated), a central regulator of the DNA damage response pathway.[5] ATM activation (indicated by phosphorylation at S1981) occurs relatively early after GZ17-6.02 exposure, initially observed perinuclearly before becoming prominent in the nucleus, coinciding with increased levels of the DNA damage marker γH2AX.[10] This ATM activation appears to be a critical upstream event, as its inhibition or knockdown significantly reduces GZ17-6.02-induced cytotoxicity and autophagy in several models.[4]

4.3. Autophagy Induction and Dependence

One of the most frequently reported effects of GZ17-6.02 is the potent induction of macroautophagy (hereafter referred to as autophagy).[4] This is characterized by increased autophagosome formation followed by autophagic flux (fusion with lysosomes).[4] The induction of autophagy is linked mechanistically to the upstream activation of the ATM-AMPK signaling axis, leading to the inhibition of the autophagy suppressor mTORC1 and modulation of the autophagy initiation kinase ULK1 (dephosphorylation at S757, phosphorylation at S317) and ATG13 (phosphorylation at S318).[4]

Critically, the induced autophagy appears to be a key mediator of GZ17-6.02's cytotoxic effects, rather than a pro-survival response. Across multiple cancer cell types and combination treatment scenarios, genetic knockdown or inhibition of essential autophagy proteins (e.g., Beclin1, ATG5, ULK1) significantly protected cells from GZ17-6.02-induced death.[4] This dependence suggests that GZ17-6.02 may trigger autophagic cell death or that the sustained, high level of autophagy induced becomes detrimental to the cancer cells. This is further supported by the finding in multiple myeloma cells that autophagy is required for the degradation of HDACs 1, 2, and 3 following GZ17-6.02 treatment.[4]

4.4. Endoplasmic Reticulum (ER) Stress

GZ17-6.02 treatment also activates the ER stress response pathway.[4] This is marked by the activation of PERK (PKR-like endoplasmic reticulum kinase) and the subsequent phosphorylation (inactivation) of the translation initiation factor eIF2α at Serine 51.[4] Similar to autophagy, ER stress signaling appears functionally linked to GZ17-6.02's activity, as knockdown of eIF2α significantly reduced both autophagosome formation and cell killing induced by the drug.[5] This indicates crosstalk between the ER stress and autophagy pathways in mediating the drug's effects.

4.5. Modulation of Signaling Pathways and Cellular Processes

GZ17-6.02 impacts a wide array of intracellular signaling pathways and processes:

• Key Activated Kinases/Pathways: ATM, AMPK, PERK.[4] NFκB activation was noted specifically in mycosis fungoides cells.[14]
• Key Inhibited/Inactivated Kinases/Pathways: mTORC1/2, AKT, ULK1 (at S757), eIF2α (at S51), Hippo pathway effectors (YAP/TAZ), JAK/STAT signaling (STAT3 Y705, STAT5 Y694), ERK1/2, various receptor tyrosine kinases (ERBB family, PDGFRβ), and c-SRC (via Y527 dephosphorylation).[4] NFκB inactivation was noted in multiple myeloma cells treated with GZ17-6.02 plus bortezomib.[4]
• HDAC Degradation (MM Cells): Autophagy-dependent degradation of HDACs 1, 2, and 3, leading to increased histone H3 acetylation and methylation.[4]
• Apoptosis Induction: GZ17-6.02 induces apoptosis, involving caspase-3 activation and PARP cleavage.[8] This is associated with modulation of BCL-2 family proteins (downregulation of anti-apoptotic BCL-XL, MCL1; upregulation of pro-apoptotic BAK, BIM) and upregulation of death receptor signaling components (CD95/FAS-L).[4] Knockdown of death pathway components (CD95, FADD, BID, caspases) confers protection against GZ17-6.02-induced cell death.[14]
• Immune Modulation: Preclinical data indicate GZ17-6.02 can decrease PD-L1 expression and increase MHCA expression on some tumor cells, potentially enhancing their immunogenicity and susceptibility to immune attack.[12]

4.6. Integrated Mechanistic Model

The diverse effects of GZ17-6.02 suggest an integrated mechanism where initial cellular insults, notably DNA damage, trigger a cascade of stress responses. ATM activation acts as a central node, propagating signals to AMPK, which in turn inhibits mTOR and promotes autophagy. Concurrently, or subsequently, ER stress pathways are activated (PERK/eIF2α). The pronounced and sustained autophagy induced by GZ17-6.02 appears crucial for its cytotoxicity, potentially leading to autophagic cell death or facilitating the degradation of essential proteins like HDACs (in MM). These stress pathways, combined with the modulation of survival signals (AKT, STAT, ERBB inhibition) and apoptosis regulators (BCL-2 family, death receptors), culminate in cancer cell death. The inhibition of super-enhancers may represent an additional layer of activity, disrupting core transcriptional programs necessary for tumor maintenance and potentially contributing to the drug's broad efficacy. The relative importance and interplay of these pathways likely vary depending on the specific cancer type and genetic context.

5. Preclinical Evidence

GZ17-6.02 has been subjected to extensive preclinical evaluation, demonstrating notable anti-tumor activity both as a single agent and in combination with various established cancer therapies across a wide spectrum of malignancies.

5.1. Monotherapy Activity

In vitro studies have consistently shown that GZ17-6.02 induces cell death in a dose-dependent manner across numerous human cancer cell lines and patient-derived xenograft (PDX) isolates. These include models of multiple myeloma (MM), prostate cancer, glioblastoma (GBM), mycosis fungoides (MF), gastrointestinal (GI) cancers (colorectal, pancreatic, hepatic, biliary), non-small cell lung cancer (NSCLC), cutaneous melanoma, uveal melanoma, sarcoma, estrogen receptor-positive (ER+) breast cancer, actinic keratoses, pediatric leukemia, and osteosarcoma.[4]

A noteworthy observation from in vitro comparisons is the apparently higher single-agent potency of GZ17-6.02 against MM cell lines compared to some solid tumor cell lines, such as prostate and NSCLC.[4] While GZ17-6.02 induced significantly more autophagosome formation in MM cells than prostate cancer cells, the subsequent autophagic flux (autolysosome formation) was comparable between the cell types.[13] This differential sensitivity could reflect varying dependencies on the pathways targeted by GZ17-6.02 and might have implications for clinical indication selection.

In vivo, GZ17-6.02 monotherapy demonstrated significant anti-tumor efficacy. In orthotopic xenograft models of pancreatic cancer, GZ17-6.02 significantly inhibited tumor growth.[9] In prostate cancer xenografts (LNCaP), single-agent GZ17-6.02 profoundly reduced tumor growth and significantly prolonged animal survival.[10] Similar significant survival benefits beyond the treatment period were observed in colorectal cancer models.[5] GZ17-6.02 also inhibited tumor growth in a subcutaneous GBM xenograft model.[7] Furthermore, pharmacokinetic studies confirmed that the individual components of GZ17-6.02 reach tumor tissues in vivo at concentrations relevant to those used in in vitro experiments.[5]

5.2. Combination Therapy Activity

A major focus of preclinical research has been evaluating GZ17-6.02 in combination with other anti-cancer agents. These studies have frequently demonstrated additive or synergistic interactions, suggesting GZ17-6.02 could enhance the efficacy of standard therapies or overcome resistance.

• Combination with Chemotherapy: GZ17-6.02 showed additive to greater-than-additive killing when combined with 5-fluorouracil (5FU) in GI tumor cells in vitro.[12] In vivo, prolonged exposure to GZ17-6.02 enhanced the efficacy of 5FU in colorectal cancer models, significantly prolonging survival.[19] It also interacted effectively with doxorubicin in sarcoma and uveal melanoma models [17] and with pemetrexed in NSCLC models (including mutant ERBB1, mutant RAS, and EGFR inhibitor-resistant cells).[24]
• Combination with Targeted Therapies:
• Proteasome Inhibitors (Bortezomib, Carfilzomib): Showed greater-than-additive killing in MM cells, including bortezomib-resistant lines.[4]
• PARP Inhibitors (Olaparib): Demonstrated greater-than-additive killing in vitro in prostate cancer cells. In vivo, the combination further suppressed LNCaP tumor growth compared to GZ17-6.02 alone, although this did not translate to significantly improved overall survival in the specific model tested.[10]
• BRAF/MEK Inhibitors (Dabrafenib/Trametinib): Additive killing observed in BRAF V600E mutant melanoma cells, including those resistant to vemurafenib.[23]
• CDK4/6 Inhibitors (Palbociclib): Additive killing demonstrated in ER+ breast cancer cells.[18]
• RTK Inhibitors: Synergistic killing observed with ERBB family inhibitors in uveal melanoma PDX isolates.[16] However, no interaction was seen with EGFR inhibitors in osimertinib-resistant NSCLC models.[24]
• Combination with Retinoids: GZ17-6.02 combined effectively with bexarotene to kill mycosis fungoides cells.[14]
• Combination with Immunotherapy: Prolonged exposure to GZ17-6.02 enhanced the efficacy of a subsequent anti-PD1 antibody in a colorectal cancer model in vivo.[19] Combination with anti-PD1 is also supported for uveal melanoma based on preclinical rationale.[16]

The broad synergistic potential observed across diverse drug classes (chemotherapy, PARP inhibitors, proteasome inhibitors, kinase inhibitors, immunotherapy) suggests GZ17-6.02 may act through mechanisms that sensitize cancer cells to other treatments, potentially by inducing cellular stress (DNA damage, ER stress) or modulating resistance pathways like autophagy.

5.3. Resistance Mechanisms

Preliminary investigation into resistance mechanisms found that colorectal cancer cells exposed long-term to GZ17-6.02 in vivo exhibited elevated expression of ERBB2 and ERBB3 receptor tyrosine kinases.[19] These resistant cells also showed reduced expression of CD95 and FAS-L. Treatment with HDAC inhibitors could enhance CD95/FAS-L levels in these resistant cells (via NFκB activation) and partially restore sensitivity to GZ17-6.02.[19]

Table 2: Summary of GZ17-6.02 Preclinical Activity

Cancer Type	Model	GZ17-6.02 Effect (Monotherapy)	Combination Agent(s)	Interaction Effect (Additive/Synergistic)	Key Mechanistic Finding / Note	Source Snippet(s)
Multiple Myeloma (MM)	In vitro (cell lines, incl. resistant)	Cytotoxic (high potency vs. solid tumors)	Bortezomib, Carfilzomib	> Additive	Autophagy-dependent HDAC degradation; ATM/AMPK/PERK activation; ULK1/mTOR/eIF2α/NFκB/Hippo inhibition	4
Prostate Cancer	In vitro (LNCaP, PC3, DU145); In vivo (LNCaP xenograft)	Cytotoxic; Tumor growth inhibition; Prolonged survival	Olaparib	> Additive (in vitro); Additive (tumor growth, in vivo); No significant survival benefit (in vivo)	ATM/AMPK/ULK1 activation; Autophagy/ER stress required for killing	10
Glioblastoma (GBM)	In vitro (GSCs); In vivo (xenograft)	Cytotoxic; Tumor growth inhibition	N/A	N/A	Downregulation of SE genes (WSCD1, ELOVL2, KLHDC8A); Affects fatty acid synthesis	7
Mycosis Fungoides (MF)	In vitro (cell lines)	Cytotoxic	Bexarotene, Vorinostat	Effective combination	Multi-factorial killing (ER stress, autophagy, death receptor, mitochondrial dysfunction)	14
Colorectal Cancer (CRC)	In vivo	Tumor growth inhibition; Prolonged survival	5-Fluorouracil (5FU)	Additive / > Additive (in vitro); Enhanced efficacy (in vivo)	ATM activation; mTOR inactivation; Autophagy	12
CRC	In vivo	N/A (prolonged exposure)	Anti-PD1 Ab	Enhanced efficacy	Resistance associated with ERBB2/3 upregulation; HDACi restores sensitivity	19
Pancreatic Cancer	In vivo (orthotopic xenograft)	Tumor growth inhibition	N/A	N/A	SE inhibition; Affects tumor stem cell markers	9
Uveal Melanoma	In vitro (PDX isolates)	Cytotoxic	Doxorubicin; ERBB inhibitors	Synergistic	ATM/AMPK/mTOR activation; YAP/TAZ/eIF2α inactivation; Reduced PD-L1	16
Cutaneous Melanoma (BRAF V600E)	In vitro (PDX isolates, incl. resistant)	Cytotoxic	Trametinib + Dabrafenib	Additive	ATM/AMPK/eIF2α activation; Reduced JAK/STAT	23
Non-Small Cell Lung Cancer (NSCLC)	In vitro (mutant ERBB1, mutant RAS, EGFRi-resistant)	Cytotoxic	Pemetrexed	Synergistic	N/A	24
NSCLC	In vitro (osimertinib-resistant)	Cytotoxic	EGFR inhibitors	No interaction observed	N/A	24
ER+ Breast Cancer	In vitro	Cytotoxic	Palbociclib	Additive	ATM/AMPK/ULK1/PERK activation; mTOR/AKT inactivation; Autophagy	18
Sarcoma	In vitro	Cytotoxic	Doxorubicin	Synergistic	N/A	24
Pediatric Leukemia / Osteosarcoma	In vitro	Cytotoxic	N/A	N/A	Dose-dependent killing	30

N/A: Not Applicable or Not Addressed in the cited snippets.

6. Clinical Development Program

The clinical development of GZ17-6.02 commenced following Investigational New Drug (IND) application clearance from the U.S. Food and Drug Administration (FDA) in November 2018.[3] The program initially focused on establishing safety, tolerability, and the RP2D in patients with advanced malignancies.

6.1. Phase 1 Trial (NCT03775525)

• Trial Design and Objectives: This was a first-in-human, Phase 1/Ib, multi-center, open-label study designed primarily to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and maximum tolerated dose (MTD) or RP2D of GZ17-6.02.[16] It included dose-escalation cohorts evaluating GZ17-6.02 monotherapy administered orally daily, as well as a combination arm evaluating GZ17-6.02 (administered orally twice daily, BID) with capecitabine in patients with metastatic hormone receptor-positive (HR+) breast cancer.[25] Preliminary efficacy was a secondary objective.[16]
• Patient Population: The trial enrolled adult patients with advanced solid tumors or lymphoma who had progressed on standard therapies.[3] The combination arm specifically targeted patients with metastatic breast cancer.[2] Enrollment was projected at 30-40 patients nationally.[3]
• Status and Timeline: The IND was cleared in November 2018.[3] The trial officially started in March 2019 [16], with the first patient dosed the same month at the HonorHealth Research Institute in Scottsdale, Arizona.[3] Multiple sources confirm that the Phase 1 evaluation has been completed.[4] One database entry notes an "unknown status" but this appears outdated given the subsequent initiation of Phase 1B studies and consistent reporting of Phase 1 completion.[16] The estimated study completion date was December 2023.[25]
• Key Outcomes:
• RP2D: The study successfully identified the RP2D as 375 mg administered orally twice daily (PO BID).[4]
• Safety and Tolerability: GZ17-6.02 demonstrated a favorable and manageable safety profile.[2] The most notable treatment-related adverse events reported were Grade 1, 2, or 3 reversible alterations in plasma liver enzyme levels.[5]
• Preliminary Efficacy: The trial provided early evidence of clinical benefit.[2] Specific anti-tumor activity was observed, including a confirmed partial response (PR) in a patient with c-MET amplified NSCLC who also experienced prolonged stable disease (SD), tumor shrinkage (>20%) in a patient with HER2 mutant NSCLC, and prolonged SD (5 months with 15% tumor mass reduction at RP2D) in a patient with uveal melanoma. Prolonged SD was also noted in other tumor types.[5]
• PK/PD: Laboratory-based PK/PD studies confirmed that all three components of GZ17-6.02 were concentrated in tumors in vivo at levels exceeding those used for in vitro studies.[5]

The successful completion of the Phase 1 trial, establishing an RP2D with a manageable safety profile and observing objective anti-tumor responses in heavily pretreated patients, provided the necessary foundation for advancing GZ17-6.02 into further clinical investigation, particularly in combination settings suggested by the preclinical data.

6.2. Phase 1B Trial: Metastatic Breast Cancer

Following the Phase 1 study, Genzada initiated a Phase 1B clinical trial specifically evaluating GZ17-6.02 in combination with capecitabine for patients with metastatic breast cancer.[2] This trial officially opened in May 2022.[2] The design involves administering GZ17-6.02 orally twice daily in combination with standard-dose capecitabine.[25] Dr. Joyce O'Shaughnessy was noted as a participating investigator.[2] No specific NCT identifier or further details on status or results for this Phase 1B trial were provided in the source materials beyond its initiation.[2]

6.3. Planned Phase 1 Trial: Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Clinical trial registries indicate plans for a Phase 1 trial (NCT06636123 / NCI-2024-09343) evaluating GZ17-6.02 monotherapy in patients with progressive mCRPC.[1]

• Trial Design and Objectives: This Phase 1 trial is designed to assess the safety, side effects, and efficacy of GZ17-6.02 in patients with mCRPC that has progressed after treatment with ADT and at least one ARPI.[27] Prior PSMA-targeted therapy or chemotherapy is allowed but not required.[27] The primary objective listed is to assess the efficacy based on the disease control rate at 6 months (DCR6), defined as radiographic progression-free survival for ≥6 months.[27] Secondary objectives include measuring biochemical response rate (PSA), duration of response, objective response rate (ORR) by RECIST v1.1, and overall survival.[27]
• Intervention: Patients are planned to receive GZ17-6.02 orally twice daily (PO BID) on days 1-28 of each 28-day cycle, for up to 6 cycles, unless disease progression or unacceptable toxicity occurs.[27]
• Status: As of October 2024, the trial was planned to start that month.[1] The NCI listing indicates the trial is designated NCI-2024-09343.[27] No information regarding enrollment initiation or current status post-October 2024 was available in the provided sources.

6.4. Amyotrophic Lateral Sclerosis (ALS) Indication

No information supporting the investigation of GZ17-6.02 for Amyotrophic Lateral Sclerosis (ALS) was found within the provided source materials.[5] The clinical trials identified focus exclusively on oncology indications (solid tumors, lymphoma, metastatic breast cancer, mCRPC). While some components like curcumin have been explored in neurodegenerative contexts, the GZ17-6.02 program itself appears oncology-focused based on the available data.

7. Conclusion

GZ17-6.02, developed by Genzada Pharmaceuticals, is an orally administered investigational drug formulated as a synthetic combination of isovanillin, harmine, and curcumin. This multi-component approach appears critical, as preclinical data consistently indicate synergistic activity exceeding that of the individual components.[5]

The compound exhibits a complex, multi-targeted mechanism of action involving the disruption of super-enhancer networks, induction of DNA damage response via ATM activation, potent modulation of autophagy and ER stress pathways, and inhibition of multiple oncogenic signaling cascades.[4] Notably, the induction of autophagy appears functionally linked to GZ17-6.02's cytotoxic effects in several cancer models.[4]

Extensive preclinical studies have validated GZ17-6.02's anti-tumor potential across a broad range of solid and hematologic malignancies, both as monotherapy and, significantly, in combination with diverse standard-of-care agents including chemotherapy, targeted therapies (PARP inhibitors, proteasome inhibitors, kinase inhibitors), and immunotherapy.[2] This broad combination potential is a key feature highlighted by the preclinical data.

The Phase 1 clinical trial (NCT03775525) successfully established an RP2D of 375 mg PO BID, demonstrated a manageable safety profile primarily involving reversible liver enzyme elevations, and provided preliminary evidence of clinical activity in patients with advanced, refractory cancers.[2] These findings supported the initiation of a Phase 1B trial in metastatic breast cancer (combination with capecitabine) and planning for a Phase 1 trial in mCRPC.[1]

In summary, GZ17-6.02 is a novel, orally available, multi-component agent with a unique, multi-pronged mechanism of action. Its broad preclinical activity, particularly in combination settings, and encouraging early clinical data (safety and preliminary efficacy) support its continued investigation as a potential new therapeutic option for various cancers. Further results from the ongoing and planned Phase 1/1B trials will be crucial in defining its clinical utility.

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