Recruiting Phase 3 Study: INVINCIBLE-3
A Multicenter, Randomized, Phase 3 Study to Assess the Efficacy and Safety of Intratumorally Administered INT230-6 (SHAO, VINblastine, CIsplatin) Compared with US Standard of Care in Adult Participants with Locally Recurrent, InoperaBLE, or Metastatic Soft Tissue Sarcomas (NCT06263231)
This recruiting study evaluates a novel, new drug product (INT230-6) administered intratumorally by an interventional radiologist or an equivalently trained physician using image guidance compared to systemically dosed US standard-of-care chemotherapy. The study endpoints are overall survival and safety.
This is a randomized, open-label, multicenter, Phase 3 study comparing the efficacy and safety of INT230-6 to any of 3 US standard-of-care therapy (pazopanib, trabectedin, or eribulin) in approximately 333 adult participants with locally recurrent, inoperable, or metastatic Soft Tissue Sarcomas (STS) who had disease progression prior to study enrollment following standard therapies, which must have included an anthracycline-based regimen unless contraindicated. Participants may also have received a maximum of 1 additional regimen. Randomization will occur after screening and eligibility confirmation.
As this is a survival study, there is no cross-over allowed from US SOC to INT230-6. Disease progression will be determined by the World Health Organization (WHO) Criteria. Participants will be prospectively stratified into 1 of 3 histologically defined aSTS strata: • leiomyosarcoma (non-uterine), • liposarcoma (dedifferentiated, myxoid, round cell and pleomorphic) • undifferentiated pleomorphic sarcoma
Planned Phase 2 Study in Triple Negative Breast Cancer (TNBC) INVINCIBLE-4-SAKK
Intratumoral INT230-6 followed by neoadjuvant immunochemotherapy in patients with early TNBC. An open-label randomized two cohort phase 2 clinical trial. (NCT06358573)
The percentage of change in pathological complete response (pCR) or the absence of cancer in a tumor prior to resection) has been recognized by FDA as a surrogate endpoint to support accelerated approval for neoadjuvant treatment of high-risk, early-stage breast cancer. The data from the INVINCIBLE-2 study helped us to understand the potential that the addition of INT230-6 to an existing or modified neoadjuvant (presurgical) treatment regimen could have on improving the pCR rate when added to the current presurgical standard of care for triple negative patients (TNBC). Our drug has the potential to reduce toxicities in these TBNC patients as well. As a result of the findings from the INVINCIBLE-2 study we have designed the INVINCIBLE-4-SAKK trial.
INVINCIBLE-4 is a randomized, open-label multicenter phase 2 clinical study to determine the clinical activity, safety, and tolerability of INT230-6 in patients with early-stage, operable TNBC. The study will allow for a sizing estimate for a Phase 3 trial in TNBC patients who undergo neoadjuvant systemic treatment. The accrual duration of the Phase 2 is expected to be 12 months, and the duration of trial therapy per patient is expected to be no more than 8 months. A non-comparative randomized design with two cohorts is being used. Both cohorts will be analyzed separately. The primary analysis will take place once all patients have had surgery. The primary endpoint of the INVINCIBLE-4-SAKK study is Pathological complete response (pCR) in the primary tumor (ypT0/Tis) and affected lymph nodes (ypN0). The study is a multi-center clinical trial with approximately 16 sites in total, Switzerland and France. A total of 54 to 60 patients are expected to be enrolled. This trial will comply with the protocol, the current version of the Declaration of Helsinki, the ICH GCP E6(R2), or ISO EN 14155 (as far as applicable), and all national legal and regulatory requirements.
Completed: INVINCIBLE-2
(IT-02)/OTT 20-11
A Phase 2 Randomized Window of Opportunity Trial Evaluating Clinical and Biological Effects of Intratumoral INT230-6 in Early-Stage Breast Cancer (NCT04781725)
Following receipt of the authorization from Health Canada, Intensity executed agreements with The Ottawa Hospital and The Ontario Institute for Cancer Research (OICR) to conduct a Phase II Randomized Trial for Intratumoral INT230-6. The study was conducted in two parts. The first portion was dose ranging. Key objectives were to understand safety of 1, 2 or 3 doses of INT230-6 compared to the standard of care, which is no treatment. The second part compared INT230-6 to saline solution intratumoral injections. The key objectives were to understand changes in the the percent necrosis from a single dose and the drug’s effect on various blood-based or tissue immune and genetic-based biomarkers. A total of 91 patients were enrolled. Patients were randomized to either INT230-6 (60), no treatment (9) or saline injection (20). Two patients were excluded.
In the INVINCIBLE-2 study Treatment with INT230-6 was generally safe and well tolerated. Adverse events were minimal and transient, most frequently including low-grade pain at the injection site. The results demonstrate that intratumoral injection of INT230-6 can induce significant necrosis in tumors following a single dose. The results support the mechanism of action for the dispersion and diffusion of cytotoxic agents causing significant tumor necrosis.
CIBERSORT analysis demonstrated positive changes in the composition of the immune cell population post-dosing of INT230-6 compared to controls, including M2 macrophages, CD4-positive memory, and naïve T cells, and activated DCs. Dendritic cells play a vital role between innate immunity and adaptive immunity and can be classified as professional antigen-presenting cells. Dendritic cells have been shown to initiate and modulate the adaptive immune response by activating both T and B lymphocytes.
In INT230-6 treated patients, significant differential gene expression was present and identified genes were associated with T cell activation, lymphocyte activation, and inflammatory response. Gene expression analysis also showed significant differential gene expression between the baseline biopsy and surgical specimens. Treatment with INT230-6 results not only resulted in an increase in CD4 T cells and NK cells within the tumor but there were associated changes in the diversity of T-cell repertoire.
Completed:
Metastatic Study IT-01
A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in Adult Subjects with Advanced Refractory Cancers (Study IT-01). (NCT03058289)
INT230-6 is a multi-component drug product specially formulated for intratumoral (IT) administration. The technology used in the product facilitates dispersion of drugs throughout the tumor and diffusion into cancer cells. Nonclinical data show increased influx of dendritic and T cells into the tumor and a robust CD8 T cell response that clears the remaining live tumor cells. FDA authorized the start of the dose escalation and phase 2 expansion study, which was completed after enrollment of 110 patients in 9 cohorts (6 cohorts of INT230-6 alone, and 3 in combination with immunotherapies).
Clinically IT doses of INT230-6 for a given tumor were set by the longest diameter or calculated tumor volume from 3 dimensions. Total tumor burden (TTB) was also calculated for each subject from all reported tumors. No tumors < 1 cm were reported or followed. Clinical data from large, resected breast cancer tumors injected with INT230-6 support the dispersion and diffusion mechanism of action.
The IT-01 study’s primary objective was to assess the safety and tolerability of multiple IT doses of INT230-6. Dose escalation was done in 5 cohorts by increasing the dose amount, frequency, and tumor loading ratio in subjects with advanced or recurrent malignancies. INT230-6 was given either once every 28 days (Cohorts A1, B1) for 5 treatments or once every 2 weeks for 5 treatments with repeat or maintenance dosing every 9 weeks (Cohorts EA, EC, EC2, EC3). A set dose limit of 175 mL was used for a 6th monotherapy cohort that also included maintenance dosing.
During the study, observations showed that subjects receiving a dose of TTB of ≥ 40% of their reported calculated TTB had better survival efficacy outcomes. TTB was calculated for each reported injected and bystander tumor identified from the baseline scan. When a tumor’s 3 dimensions were available, the modified ellipsoid model was used (LxWxDx0.63).
Safety was assessed by the rate of Grade ≥ 3 adverse events (AEs) attributed to INT230-6 and not the underlying disease. Secondary objectives were to 1) assess the preliminary efficacy of INT230-6 by measuring the disease control rate (DCR) based on the Response Evaluation Criteria in Solid Tumors (RECIST) and immune RECIST (iRECIST) criteria, 2) characterize the pharmacokinetic (PK) profile of the 3 INT230-6 components (cisplatin, vinblastine sulfate, and SHAO dispersion enhancer).
INT230-6 was also to be tested in combination with additional agents that had fixed dosing schedules. Inclusion and exclusion criteria were modified during the study. Blood and tumor tissue biomarkers were also assessed throughout the study. We have reported safety, immune response and efficacy data from patients treated during the escalation and phase 2 portions of our study in refractory metastatic patients at major cancer meetings. The selection committees from the world’s most important oncology conferences’ have chosen our data for oral podium discussion by independent key opinion leaders. These medical conferences include the annual American Society of Clinical Oncology (ASCO) conference, the annual Society for Immunotherapy of Cancer (SITC) conference, the annual Connective Tissue Oncology Society (CTOS, which is for sarcoma) and the annual San Antonio Breast Cancer Symposium (SABCS). Please view our presentation and results on the Presentations page.
In our metastatic study IT-01, a high percentage of highly refractory patients treated with INT230-6, whose cancer had progressed following multiple drug treatments – a median of 3 and primarily all approved therapies – have shown disease stabilization. There has also been a significant increase in overall survival compared to what was expected for this severely ill population. Further, exploratory analysis indicates that receiving intratumoral INT230-6 where the total drug volume (mL) administered over 5 sessions is equivalent or greater than approximately 40% of the patient’s baseline incoming total tumor burden (measured in cubic centimeters from scans) leads to a further increase in survival compared to historical data.
INT230-6 dosing is determined from scan data. The to-be-injected dose is based by either the tumor longest diameter (for tumors under 9 cm) or the total calculated volume based on 3 dimensions using the modified ellipsoid formula. The observation made in mouse models that a specific drug dose per tumor volume is needed to saturate the injected tumors completely appears to be highly relevant in humans. Following treatment, many subjects’ tumors increase in size over baseline, then regress on subsequent scans. Several patients showed some size reduction of one or more non injected lesions in lymph nodes, liver, lung, perineum, and retroperitoneal areas (abscopal effects to visceral lesions). Our drug has been well tolerated, with most adverse events being of mild or moderate i.e. low grade (1 or 2) based on CTCAE scoring.