Intratumoral Injection Shows Antitumor Activity and Safety in Sarcoma

An intratumoral therapy, INT230-6, demonstrated its dual-mechanism antitumor activity as a monotherapy and in combination with ipilimumab (Yervoy) in patients with metastatic sarcomas, according to results from an oral presentation at the 2022 Connective Tissue Oncology Society (CTOS) Annual Meeting.¹

As part of the open-label phase 1/2 IT-01 study (NCT03058289), INT230-6 showed its capability to target cancer cells directly and cause an immune antitumor response in soft tissue sarcoma (STS) when injected into a tumor. The treatment was well tolerated and greater than 95% of the active agents remained in the tumor relative to intravenous dosing at 1 to 6 hours.

“Preliminary data suggests that INT230-6, as a monotherapy or in combination with the immune checkpoint blocker ipilimumab, demonstrates direct tumor killing in STS and elicits an anti-cancer immune response within the injected tumor,” Matthew Ingham, MD, assistant professor of medicine in the Division of Hematology and Oncology at Columbia University Vagelos College of Physicians and Surgeons, and a principal investigator for the trial, said in a statement.²

INT230-6 is a novel therapy comprised of cisplatin and vinblastine, co-formulated with the amphiphilic molecule SHAO, that can be injected into a tumor and diffuse into surrounding cancer cells.1 In the INVINCIBLE study (NCT04781725) of patients with breast cancer, it showed evidence of up to 95% tumor necrosis and an increase in tumor-infiltrating lymphocytes.³

The IT-01 trial enrolled patients with advanced solid tumors including sarcoma and breast cancer in the INT230-6 monotherapy cohort and those with breast cancer, hepatocellular cancer, and sarcoma to receive INT230-6 plus ipilimumab. The presented data reported on 15 patients with sarcoma who received monotherapy and 14 who received the ipilimumab combination. The demographics of those enrolled were similar whether they received monotherapy or the combination: the monotherapy group had a median of 3 prior therapies while the combination group had a median of 4 prior therapies. The majority of patients had an ECOG performance score of 1.¹

The primary end point was the rate and severity of treatment-related adverse events (TRAEs) of grade 3 or higher for up to 5 years. Secondary end points included preliminary control or regression of tumor size and several key pharmacokinetic parameters, and overall survival (OS) was an exploratory end point.

In terms of TRAEs in the INT230-6 monotherapy group, there was 1 grade 3 incidence each of localized tumor-related pain, fatigue, anemia, and hyponatremia.¹ Localized tumor-related pain was the most common any-grade TRAE, occurring in 12 patients (80.0%), followed by nausea in 6 patients (40.0%) and fatigue in 5 patients (33.3%). There was 1 incidence of treatment-related grade 3 anemia in the INT230-6 plus ipilimumab group. The most common any-grade TRAEs were localized tumor-related pain in 6 patients (42.9%), fatigue in 5 patients (35.7%), and nausea in 4 patients (28.6%) No grade 4 or 5 TRAEs were reported in either group.

A scan of a chordoma that was injected with INT230-6 monotherapy showed a decrease in size from 55.65 mm × 32.48 mm to 47.5 mm × 18.78 mm at 6 months, which was considered a partial response based on WHO criteria, but stable disease based on RECIST criteria.

INT230-6’s components, cisplatin and vinblastine, are known to have immune-activating effects. At day 28 of treatment following 2 doses of INT230-6, investigators observed activation of CD3, CD4 and CD8 T cells within the tumors of 2 selected patients receiving monotherapy, one with ovarian cancer and another with liposarcoma.

Though this study had no control arm, investigators compared overall survival (OS) outcomes with other phase 1/2 studies of patients with sarcoma to derive a control arm median OS of 205 days.² Those who received INT230-6 monotherapy had a median OS of 649 days (CI, 195-1352), and in the 11 out of 15 patients who received a cumulative dose of greater than 40% of their total tumor burden, the median OS was 715 days (CI, 649-1352).¹ The median OS was not reached in the INT230-6 plus ipilimumab group at a median follow-up of 345 days. Twelve out of these 14 patients remained alive at data cut-off.

Based on the safety and early efficacy demonstrated in this trial, Intensity Therapeutics planned a randomized phase 3 trial to investigate the efficacy of this agent.

“The promising data supports our belief that INT230-6 could show clinical benefit with lower levels of off-target side effects compared to standard chemotherapies,” Lewis H. Bender, president and chief executive officer of Intensity Therapeutics, stated.² “We have designed a randomized phase 3 trial protocol to evaluate INT230-6 versus standard of care in patients with advanced STSs and look forward to initiation of the study.”

The proposed phase 3 trial, which is intended to begin in 2023, will include patients who have received 1 or 2 prior lines of therapy for locally advanced or metastatic STS including doxorubicin.¹ Up to 332 patients will be randomly assigned 2:1 to receive either INT230-6 or standard of care, which could be pazopanib (Votrient), trabectedin (Yondelis), or eribulin (Halaven). The primary end point would be OS, with secondary end points including safety and quality of life.

_References:

_{1. Intratumoral INT230-6 (cisplatin, vinblastine, Shao) alone or with ipilimumab prolonged survival with favorable safety in adults with refractory sarcomas. Presented at: 2022 Connective Tissue Oncology Society Annual Meeting; November 18-21, 2022; Vancouver, Canada. Accessed November 21, 2022. https://bit.ly/3Vb9s3w}

_{2.Intensity Therapeutics reports use of INT230-6 alone or in combination with ipilimumab shows evidence of direct tumor necrosis and promising overall survival results in adult subjects with metastatic sarcomas at the Connective Tissue Oncology Society (CTOS) 2022. Intensity Therapeutics. November 18, 2022. Accessed November 21, 2022. https://prn.to/3Es2b8L}

_{3. Arnaout A, Spears M, Awan AA, et al. Intratumoral (IT) INT230-6 can cause tumor necrosis in vivo: Preliminary results of a phase II randomized presurgical window-of-opportunity study in early breast cancers (the INVINCIBLE study). J Clin Oncol. 2022;40(suppl 16):605. doi:10.1200/JCO.2022.40.16_suppl.605}