A Study to Investigate Efficacy & Safety of Intratumoral INT230-6 Compared to US Standard of Care in Adults With Soft Tissue Sarcomas (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 Adults With Locally Recurrent, InoperaBLE, or Metastatic Soft Tissue Sarcomas (INVINCIBLE-3)

To compare Overall Survival (OS) for INT230-6 vs United States (US) Standard of Care (SOC) in participants with unresectable or metastatic liposarcoma, undifferentiated pleomorphic sarcoma or leiomyosarcoma who have disease progression prior to study enrollment following no more than 2 standard therapies, which must have included an anthracycline-based regimen, unless contraindicated, and then a maximum of 1 additional regimen.

Inclusion Criteria:

1. Participant is of any sex and must be ≥ 18 years old and provide written informed consent to participate in the study.

   Type of Participant and Disease Characteristics

2. Histologically proven, unresectable, locally advanced, or metastatic Soft Tissue Sarcoma (STS) only of the following subtypes: liposarcoma (dedifferentiated, myxoid, round cell or pleomorphic), leiomyosarcoma, and undifferentiated pleomorphic sarcoma. Participant must have a pathology report indicating the diagnosis of their STS.

3. Participant must have received at least 1 line of therapy for a STS and must have progressed following anthracycline-based or alternative standard therapies, except if medically contraindicated or refused by participant. Participant cannot have received more than 2 prior regiments for unresectable, locally advanced or metastatic STS.

4. Participant must have measurable disease per RECIST 1.1 criteria.

5. Participant must have at least 1 target tumor suitable for injection using routine image guidance ≥ 2 cm measurable by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI).

6. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (see Section 11.7).

7. Participant must have adequate organ function as defined by screening laboratory values that must meet the following criteria:

   1. Neutrophils ≥ 1500/μL (≥ 1.5× 109/L).
   2. Prothrombin Time (PT), and International Normalized Ratio (INR) ≤ 1.5× Upper Limit of Normal (ULN), platelets ≥ 100,000/μL (≥ 10× 109/L); hemoglobin ≥ 9 g/dL. Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within the last 2 weeks.
   3. Creatinine within normal range; or calculated creatinine clearance > 50 mL/min by the Cockcroft-Gault equation.
   4. Alanine Aminotransferase (ALT) Serum Glutamic-Oxaloacetic Transaminase (SGOT)/ Aspartate Aminotransferase (AST) Serum Glutamic-Pyruvic Transaminase (SGPT) ≤ 2.5× ULN without, and ≤ 5× ULN with hepatic metastases.
   5. Bilirubin ≤ 1.5× ULN (except participants with Gilbert's syndrome, who must have total bilirubin < 3.0 mg/dL [< 52 µmol/L]).
   6. Creatine phosphokinase < 2.5× ULN Sex and Contraceptive/Barrier Requirements

8. A female participant is eligible to participate if she is not pregnant (as demonstrated by pregnancy testing prior to each treatment; performed at least monthly), not breastfeeding, and at least 1 of the following conditions applies:

   1. Not a Woman of Childbearing Potential (WOCBP). Women of non-childbearing potential are defined as women with functioning ovaries with a documented history of tubal ligation or hysterectomy or females who are post menopausal, as defined by 12 months of spontaneous amenorrhea with an appropriate clinical profile, e.g., age appropriate, > 45 years, in the absence of hormone replacement therapy. In questionable cases, a blood sample for Follicle Stimulating Hormone (FSH) and estradiol will be obtained to confirm childbearing potential.
   2. A WOCBP who may become pregnant or who is sexually active with a partner and who could become pregnant agrees to use a highly effective form of contraception during the study and for at least 7 months after the end of study intervention (see Section 11.5.2 for highly effective methods of contraception).

9. Male participants with female partners of childbearing potential must agree to use contraception and refrain from sperm donation during the study and for 6 months after the end of study intervention (Section 11.5.2.2).

Exclusion Criteria:

Informed Consent:

1. Adult participants who lack capacity to consent without a legally authorized representative will be excluded from this study.

   Medical Conditions:

2. Prior primary or metastatic brain or meningeal tumors unless clinically and radiographically stable as well as off-steroid therapy for at least 2 months.

3. History of severe hypersensitivity reactions to US SOC agents and vinblastine or cisplatin or other products of the same class and their excipients.

4. Histologically proven, unresectable, locally advanced or metastatic STS subtypes other than those specified, for example excluded subtypes include liposarcoma (well differentiated), desmoid or dermatofibrosarcoma protuberans.

5. Other prior malignancy, except for adequately treated basal or squamous cell skin cancer or superficial bladder cancer, or any other cancer from which the participant has been disease-free for at least 2 years.

6. Underlying medical condition that, in the investigator's opinion, will make the administration of study intervention hazardous or obscure the interpretation of toxicity determination or Adverse Events (AEs).

7. Concurrent medical condition requiring the use of immunosuppressive medications, or systemic corticosteroids (topical steroids are permitted); systemic corticosteroids must be discontinued at least 4 weeks prior to dosing.

   Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if the participant is on a stable dose. Non-absorbed intra-articular steroid injections will be permitted. Use of steroids as prophylactic treatment for participants with contrast allergies to diagnostic imaging contrast dyes will be permitted.

8. Participants who require uninterrupted anticoagulants of any type or is on daily aspirin therapy or NSAIDS.

9. Known significant chronic liver disease, such as cirrhosis or active hepatitis (potential participants who test positive for hepatitis B surface antigen or hepatitis C antibodies are allowed provided they do not have active disease requiring antiviral therapy).

10. Myocardial infarction within 6 months before enrollment, New York Heart Association Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease or electrocardiographic evidence of acute ischemic or active conduction system abnormalities.

11. Uncontrolled intercurrent illness including, but not limited to, poorly controlled hypertension or diabetes, ongoing active infection or psychiatric illness/social situation that may potentially impair the participant's compliance with study procedures.

12. Participants with a Corrected QT interval (QTc) of >450 ms for men and >470 ms for women, or with a history of serum electrolyte abnormalities known to prolong the QT interval such hypocalcemia, hypokalemia, and hypomagnesemia, or a family or personal history of congenital long QT syndrome.

13. Participants actively receiving therapy with strong Cytochrome P450 3A4 isoenzyme (CYP3A4) inhibitors (e.g, erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil).

14. Participants actively receiving therapy with medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study intervention.

    Prior/Concomitant Therapy

15. Prior chemotherapy or immunotherapy (tumor vaccine, cytokine or growth factor given to control the cancer: systemic or IT) must have been completed at least 4 weeks prior to dosing (with the exception of kinase inhibitors or other short half-life drugs, a 2-week washout is acceptable prior to treatment) and all AEs have either returned to baseline or stabilized. Note: participants who have received prior platinum therapy are eligible irrespective of their response. If participant had received one of the 3 US SOC study regimens prior to enrollment, that previous US SOC cannot be assigned in this study.

16. Prior systemic radiation therapy (IV, intrahepatic or oral) completed at least 4 weeks prior to study intervention administration. Prior focal radiotherapy completed at least 2 weeks prior to study intervention administration.

    a. Prior major treatment-related surgery completed at least 4 weeks prior to study intervention administration.

17. Use of other investigational drugs (drugs not marketed for any indication) within 28 days prior to study intervention administration.

18. Received a live vaccine within 6 weeks of first dose of study intervention.

19. Received a Coronavirus Disease (COVID-19) vaccine less than 1 week prior to dosing (Cycle 1/Day 1) and/or during the study received a COVID-19 vaccine or booster less than 3 weeks ahead of a tumor assessment.

    Other Exclusion Criteria

20. Pregnancy Exclusion: A WOCBP who has a positive pregnancy test (e.g., within 72 hours) prior to treatment. If a urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.