AVA6000 Granted FDA Orphan Drug Status for Soft Tissue Sarcoma

Pipeline Report: September 2022

The FDA has granted an orphan drug designation to AVA6000, a modified form of doxorubicin, for the treatment of patients with soft tissue sarcoma.



The FDA has granted an orphan drug designation to AVA6000, a modified form of doxorubicin, for the treatment of patients with soft tissue sarcoma, according to a press release issued by Avacta Group plc.1

AVA6000 is a therapeutic product based on proprietary pre|CISION technology that contains a substrate that is sensitive to cleavage by fibroblast activation protein α (FAP).2 Specifically, the agent is comprised of a doxorubicin molecule that is covalently bonded to a dipeptide, which is designed to be susceptible to hydrolysis by FAP but is resistant to hydrolysis by closely related and wider mammalian peptidases.

The agent can directly deliver doxorubicin to the tumor microenvironment, while exposing the patient to fewer associated adverse effects. The primary mechanism of action of doxorubicin is thought to encompass stabilization of a topoisomerase-II-DNA cleavable complex through non-specific DNA-intercalation.

“We are delighted to receive orphan drug designation from the FDA for AVA6000, which is a reflection of the high quality of the preclinical data and the potential benefit the pre|CISION platform can bring to cancer patients,” Dr Alastair Smith, chief executive officer of Avacta Group, stated in a press release.1 “This designation provides tax credits and other incentives for drug developers addressing rare diseases. Most notably, the orphan drug designation will give Avacta, if AVA600 is approved for treatment of soft tissue sarcoma, 7 years of market exclusivity in the United States, which is a significant commercial advantage.”

In human tumor cell lines, in vitro cytotoxicity assessments revealed that AVA6000 was between 80-fold and 4000-fold less cytotoxic than doxorubicin.2 Many in vivo studies done in tumors with high FAP levels have demonstrated that AVA6000 resulted in a significant reduction in tumor volume and increase in survival in a dose-dependent manner.

Specifically, in a PDX model of osteosarcoma, the agent was found to decrease tumor volume; no significant effect was observed with doxorubicin.

In an open-label, first-in-human, phase 1 study (NCT04969835), investigators will examine the safety, tolerability, pharmacokinetics, and early efficacy of AVA6000 in patients with metastatic solid tumors.3

The trial enrolled patients who were at least 18 years of age and who had histological or cytologic confirmation of locally advanced and/or metastatic pancreatic cancer, colorectal cancer, non–small cell lung cancer, squamous cell carcinoma of head and neck, ovarian cancer, breast cancer, soft tissue sarcoma, and bladder cancer who have relapsed or progressed on standard-of-care treatment or who are intolerant or not amenable to such treatment.

Patients needed to have a life expectancy of longer than 12 weeks, an ECOG performance status of 0 or 1, and acceptable hematologic, liver, and renal function.

If patients received trastuzumab (Herceptin) within 7 months of the planned day 1 of cycle 1 of infusion with AVA6000, had clinically significant or untreated central nervous system metastases in need of treatment, leptomeningeal disease, a history of an active other malignancy, or uncontrolled hypertension, they were excluded.

In the phase 1a portion of the research, participants will be administered escalating doses of AVA6000 in accordance with a 3+3 design, with a starting dose of 80 mg/m2 once every 3 weeks beginning on day 1 of cycle 1. Treatment was given until progressive disease, intolerable toxicities, withdrawal from treatment for other reason, maximum lifetime cumulative exposure to doxorubicin, or death.

For phase 1b, participants will be given the recommended phase 2 dose (RP2D) of the investigative agent once every 3 weeks beginning on day 1 of cycle 1. One of 3 tumor types will be selected based on the evaluation of the phase 1a findings.

The primary outcome measures of the study include the number of patients with dose-limiting toxicities (DLTs), percentage of those with DLTs of AVA6000 during the DLT period, identification of the maximum tolerated dose or the RP2D, and the percentage of patients with adverse effects at the RP2D of the agent in tumor-specific expansion arms.

Secondary outcome measures include maximum drug concentration of AVA6000 and doxorubicin, area under the concentration vs time curve of the 2 agents, elimination half-life of the agents, renal clearance of the agents, objective response rate, duration of response, progression-free survival, and overall survival.

In August 2021, the company announced that the first patient had received their first dose of AVA6000 at The Royal Marsden NHS Foundation Trust.4 In June 2022, it was announced that the phase 1 trial would advance to the third dose cohort.5

This decision followed a review done by a Safety Data Monitoring Committee (SDMC) comprised of clinicians recruiting patients who examined safety data from the second cohort of the trial who received AVA6000 at 120 mg/m2. The committee recommended that the trial continue as planned and escalate to the next dose of 160 mg/m2.

“The recommendation from the SDMC to initiate dosing in cohort 3 with 160 mg/m2 of AVA6000 is an endorsement of the emerging safety and tolerability profile in the patients enrolled in this study to date,” Neil Bell, chief development officer of Avacta, stated in a press release at the time. “We look forward to providing additional updates as the dose-escalation phase of the trial progresses.”


  1. AVA6000 receives orphan drug designation from the US Food and Drug Administration. News release. Avacta Group plc. September 5, 2022. Accessed September 7, 2022. https://bit.ly/3BpbE0t
  2. McLaughlin F, Poplawski SE, Sanford DG, etal. Abstract 1815: AVA6000, a novel precision medicine, targeted to the tumor microenvironment via fibroblast activation protein (FAP) mediated cleavage. Cancer Res. 2022;82(suppl 12):1815. doi:10.1158/1538-7445.AM2022-1815
  3. A study evaluating the safety, pharmacokinetics and early efficacy of AVA6000 in solid tumours. ClinicalTrials.gov. Updated April 6, 2022. Accessed September 7, 2022. https://clinicaltrials.gov/ct2/show/NCT04969835
  4. Avacta announces first patient dosed in AVA6000 pro-doxorubicin phase 1 clinical trial. News release. Avacta Group plc. August 11, 2021. Accessed September 7, 2022. https://bit.ly/3TOBtOD
  5. Avacta announces second dose escalation in the phase I clinical study of AVA6000 pro-doxorubicin. News release. Avacta Group plc. June 29, 2022. Accessed September 7, 2022. https://bit.ly/3ewWq06
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