AVA6103
Avacta's second pre|CISION-platform peptide-drug conjugate — a fibroblast activation protein (FAP)-cleavable peptide linker masking exatecan, the topoisomerase-I payload behind the deruxtecan ADC class. First patient dosed in the Phase 1 FOCUS-01 trial (NCT07454642) on March 31, 2026, with preclinical data presented at AACR 2026.
What is AVA6103?
AVA6103 is Avacta Therapeutics' second clinical peptide-drug conjugate (PDC) built on the pre|CISION platform. It pairs exatecan — a topoisomerase-I inhibitor and the active warhead family used in trastuzumab deruxtecan (Enhertu), datopotamab deruxtecan, patritumab deruxtecan, and ifinatamab deruxtecan — with a fibroblast activation protein alpha (FAPα)-cleavable peptide linker that masks the payload in circulation. FAPα is a serine protease highly expressed on cancer-associated fibroblasts in many solid tumors but minimally expressed in healthy adult tissue, providing a tumor-microenvironment-selective deconjugation switch. AVA6103 is described by Avacta as a 'sustained-release' PDC, distinct from the AVA6000 (FAP-doxorubicin) chemistry by virtue of a prolonged intratumoral payload-release profile. The Phase 1 FOCUS-01 trial (NCT07454642) began enrollment on March 31, 2026, targeting pancreatic ductal adenocarcinoma, cervical/vulvar, gastric/GEJ adenocarcinoma, and small-cell lung carcinoma. Preclinical data presented at AACR 2026 (abstract #5846) reported activity across low-to-high FAP-expression patient-derived xenografts, with a higher reported tumor selectivity index than a synthetic Enhertu comparator arm — a company-defined comparator, not a head-to-head trial.
What AVA6103 Is Investigated For
AVA6103 is the second clinical molecule from Avacta's pre|CISION FAP-activated PDC platform, swapping the AVA6000 doxorubicin payload for exatecan — the topoisomerase-I inhibitor whose deruxtecan derivative powers the most commercially successful ADC class in oncology. The strategic rationale is clear: exatecan provides broader tumor-type relevance than anthracyclines, a strong bystander effect for heterogeneous FAP expression, and a payload that lipophilic free exatecan could never achieve as a small molecule because of dose-limiting myelotoxicity. Preclinical AACR 2026 disclosures describe a 'sustained-release' intratumoral payload profile, faster tumor penetration, and a higher tumor selectivity index than a synthetic Enhertu comparator. Phase 1 FOCUS-01 (NCT07454642) is a 144-patient open-label dose-escalation and expansion study using BOIN methodology across Q3W and Q2W schedules. Honest caveats: AVA6103 has zero peer-reviewed publications, no human PK or efficacy data yet, and the Enhertu comparator was a synthetic arm rather than a randomized head-to-head. The FAP-activated PDC concept itself is still proving translational viability — AVA6000 reached Phase 1 in 2022–2023 with credible early activity in salivary gland cancer, but the broader FAP-PDC class has yet to deliver a registered therapy. AVA6103 should be understood as an early-stage platform-validation asset, not a near-term cancer therapy.
History & Discovery
Avacta Therapeutics developed the pre|CISION platform as a peptide-drug-conjugate strategy in which a FAPα-cleavable peptide linker masks a cytotoxic payload in circulation and selectively releases it within the tumor stroma. AVA6000 (FAP-doxorubicin), the first clinical asset on the platform, entered Phase 1 in 2022–2023 and reported its first clinically meaningful activity signals — including durable responses in salivary gland cancer — through 2024–2026 conference presentations. AVA6103 was developed as the platform's second clinical molecule, pairing the same FAP-cleavable linker chemistry with exatecan rather than doxorubicin. The payload switch was driven by exatecan's positioning as the dominant ADC warhead class in oncology circa 2023–2026: trastuzumab deruxtecan (Enhertu), datopotamab deruxtecan, and the broader deruxtecan family of ADCs have validated the topoisomerase-I payload class commercially and clinically. By porting that payload onto the FAP-activated PDC chassis, AVA6103 aims to reach FAP-rich stromal tumors — pancreatic, cervical/vulvar, gastric/GEJ, and small-cell lung — that are less well served by current ADC target antigens. The first preclinical disclosures arrived at AACR 2026 (abstract #5846, presented April 21, 2026), describing tumor selectivity, payload concentration, and antitumor activity in multiple patient-derived xenograft models versus a synthetic Enhertu comparator arm. The Phase 1 FOCUS-01 trial (NCT07454642) opened enrollment with first patient dosed on March 31, 2026 across sites in Virginia, Texas, and Michigan, with initial human data expected later in 2026.
How It Works
Exatecan is a strong tumor-killing drug from the same family used in Enhertu (Trastuzumab deruxtecan). AVA6103 carries exatecan with a peptide 'safety lock' that only opens at tumor sites — specifically where an enzyme called FAP (fibroblast activation protein) is found on cells that surround and support tumors. The peptide gets cleaved at the tumor, releasing active drug locally with less spillover to healthy tissue.
AVA6103 is a peptide-drug conjugate consisting of exatecan linked via a FAPα-cleavable peptide bond. FAPα is a dipeptidyl-peptidase-family serine protease whose expression on cancer-associated fibroblasts is restricted to tumor stroma and sites of active fibrosis, with minimal expression in healthy adult tissues — providing the differential cleavage signal that defines the pre|CISION platform. The payload, exatecan, is a camptothecin analog roughly 10-fold more potent than SN-38 (irinotecan's active metabolite). It traps topoisomerase-I-DNA cleavage complexes, generating single-strand DNA breaks that collapse replication forks and trigger apoptosis. Exatecan as a free small molecule was abandoned in oncology development because of dose-limiting myelosuppression; payload-conjugation strategies — both ADCs (Enhertu's DXd) and now FAP-activated PDCs — were designed specifically to deliver this potency without the systemic toxicity ceiling. Avacta describes AVA6103 as a 'sustained-release' PDC, suggesting prolonged intratumoral payload availability rather than burst release. Preclinical AACR 2026 disclosures reported a tumor selectivity index roughly three-fold higher than a synthetic Enhertu comparator arm, with tumor peak concentrations more than one log greater and faster tumor penetration. These claims are sourced from a company-defined comparator within a preclinical study, not from a randomized clinical head-to-head; they should be read as platform-validation signal rather than clinical-superiority evidence.
Evidence Snapshot
Human Clinical Evidence
First patient treated March 31, 2026 in FOCUS-01 (NCT07454642). No human PK, safety, or efficacy data published.
Animal / Preclinical
Preliminary. AACR 2026 abstract #5846 reports activity across multiple patient-derived xenografts spanning low-to-high FAP expression and improved tumor selectivity index versus a synthetic Enhertu comparator.
Mechanistic Rationale
Strong. FAP-stromal-targeting and topoisomerase-I payload chemistry are both individually well-characterized. The translational track record of the broader FAP-PDC class remains unproven.
Research Gaps & Open Questions
What the current literature has not yet settled about AVA6103:
- 01Human PK, safety, and tolerability — all to be defined in FOCUS-01.
- 02Linker cleavage kinetics in human tumors — whether sufficient FAPα activity exists across the targeted tumor types to drive therapeutic exatecan release.
- 03Comparative activity versus deruxtecan ADCs — the AACR 2026 comparator was synthetic, not a randomized head-to-head.
- 04Optimal tumor-type selection — pancreatic, cervical, gastric, and SCLC are being explored in parallel, with response heterogeneity expected.
- 05ILD signal monitoring — whether the topoisomerase-I payload carries the same ILD risk in a PDC format as it does in the deruxtecan ADC class.
Forms & Administration
Intravenous infusion in FOCUS-01. Investigational. Not commercially available. No compounded or research-chemical sources are legitimate.
Dosing & Protocols
The ranges below reflect protocols commonly discussed in the literature and by clinicians — not a prescription. Actual dosing for any individual should be determined by a qualified healthcare provider who knows the patient.
Typical Range
FOCUS-01 dose-escalation pending. Both Q3W and Q2W schedules are being explored using BOIN methodology.
Frequency
IV infusion every 2 or 3 weeks depending on cohort.
Timing Considerations
No specific timing requirements: can be administered at any time of day, with or without food, and is not tied to exercise timing. Consistency matters more than the specific clock — dose at roughly the same time each day (or same day each week, for weekly protocols) to keep exposure steady.
Cycle Length
Standard oncology cycle structure per FOCUS-01 protocol.
Protocol Notes
AVA6103 is in early clinical development and is not commercially available. Eligible patients in FAP-expressing solid tumors may discuss FOCUS-01 enrollment with their oncologist.
AVA6103 is investigational and Phase 1 stage. Oncology indication; specialty oncology supervision required for any clinical trial participation.
Timeline of Effects
Onset
Standard cycle response assessment — initial response evaluation typically at 6–9 weeks (2–3 cycles).
Peak Effect
To be characterized in Phase 1 expansion and any future Phase 2 cohorts.
After Discontinuation
Pharmacological clearance per exatecan PK; long-term durability data not yet available.
Common Questions
Who AVA6103 Is NOT For
- •Oncology trial enrollment only — outside FOCUS-01, no legitimate access.
- •Pregnancy and breastfeeding — chemotherapy contraindication.
- •Severe baseline myelosuppression — exatecan-class payloads carry myelotoxicity risk.
- •Active or prior interstitial lung disease — class concern carried over from deruxtecan ADCs that share the topoisomerase-I payload family.
- •Known hypersensitivity to camptothecin-class drugs or peptide conjugates.
Drug & Supplement Interactions
No drug interaction profile is established. Exatecan-class payloads are partially metabolized by CYP3A4 and UGT enzymes (extrapolating from related camptothecin pharmacology), so co-administration of strong CYP3A4 modulators or UGT-affecting agents is a theoretical concern. FOCUS-01 protocol exclusions will define the practical interaction list as the program progresses.
Safety Profile
Common Side Effects
Cautions
- • Investigational — Phase 1 stage with no published human data yet
- • Oncology drug — managed under specialty oncology care only
- • Exatecan/topoisomerase-I payloads carry interstitial lung disease (ILD) signal seen across the deruxtecan ADC class — relevance to AVA6103 unknown
What We Don't Know
Human safety, tolerability, PK, and activity profile — all to be characterized in FOCUS-01 (NCT07454642).
Legal Status
United States
Investigational — not FDA-approved. Phase 1.
International
Investigational across major regulators.
Sports & Competition
Not relevant — oncology indication.
Regulatory status changes over time. Verify current local rules with a qualified professional.
Myths & Misconceptions
Myth
AVA6103 is Enhertu without the antibody.
Reality
AVA6103 shares the exatecan payload family with Enhertu's DXd, but the targeting strategy is fundamentally different. Enhertu targets HER2 on the tumor cell surface; AVA6103 targets FAP on stromal cancer-associated fibroblasts. The tumor populations that respond — and the resistance mechanisms — are not interchangeable.
Myth
Because AVA6103 uses a popular payload, it will work in many cancers.
Reality
Payload identity does not determine clinical success — delivery does. Whether AVA6103 reaches therapeutic exatecan concentrations in human tumors depends on FAPα expression density, tumor accessibility, and linker cleavage efficiency in human biology. The track record of FAP-activated drug delivery in clinical trials is still being written.
Myth
Avacta data showing AVA6103 beats Enhertu means it's already superior.
Reality
The AACR 2026 comparator was a synthetic Enhertu arm in preclinical xenografts — a useful internal benchmark, not a randomized human comparison. Preclinical superiority signals routinely fail to translate. Treat the preclinical data as platform validation, not clinical superiority.
Published Research
5 studiesAvacta announces first patient treated in Phase 1 FOCUS-01 trial of FAP-Exd (AVA6103), a sustained-release pre|CISION exatecan peptide drug conjugate
Avacta press release (March 31, 2026) announcing the first patient dosed in FOCUS-01 (NCT07454642) — the Phase 1 dose-escalation and expansion study of AVA6103, the company's second pre|CISION peptide-drug conjugate. Describes the asset as a 'sustained-release' exatecan PDC distinct in chemistry from AVA6000 (FAP-doxorubicin).
FOCUS-01 (NCT07454642): A Phase 1, Open Label, Dose-Escalation and Expansion Study to Evaluate Safety, Pharmacokinetics and Initial Therapeutic Activity of AVA6103
AACR 2026 #5846 — AVA6103 is a FAP-enabled pre|CISION peptide-drug conjugate delivering sustained release of exatecan in the tumor microenvironment with potent antitumor activity
Topoisomerase I Inhibitors as ADC Payloads (review)
Background review on topoisomerase-I inhibitor payloads in antibody-drug conjugates, including the deruxtecan (DXd) class and the rationale for exatecan-derivative payloads in modern targeted oncology delivery.
Phase I AVA6000 (AACR 2024 #CT188) — A Phase I trial of AVA6000, a peptide-drug conjugate of doxorubicin selectively activated by FAP in the tumor microenvironment
Quick Facts
- Class
- FAP-Activated Peptide-Drug Conjugate
- Tier
- D
- Evidence
- Limited
- Safety
- Limited Data
- Updated
- May 2026
- Citations
- 5PubMed
Also known as
Tags
Related Goals
Evidence Score
Clinical Trials
View Clinical TrialsLinks to ClinicalTrials.gov for reference. Listing does not imply endorsement.