A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in Adult Subjects With Advanced Refractory Cancers
Brief SummaryThis study evaluates the intratumoral administration of escalating doses of a novel, experimental drug, INT230-6. The study is being conducted in patients with several types of refractory cancers including those at the surface of the skin (breast, squamous cell, head and neck) and tumors within the body such (pancreatic, colon, liver, lung, etc.). Sponsor also plans to test INT230-6 in combination with anti-PD-1 and anti-CTLA-4 antibodies.
Detailed DescriptionINT230-6 is comprised of a 3 agents in a fixed ratio - a cell permeation enhancer and two, potent anti-cancer payloads (cisplatin and vinblastine sulfate). The penetration enhancer facilitates dispersion of the two drugs throughout injected tumors and enables increased diffusion into cancer cells. (Nonclinical safety studies showed no findings following drug injection into healthy tissues.) Historically physicians administer the two active drugs comprising INT230-6 by intravenous (IV) infusion to achieve a systemic blood level at the limit of tolerability. The objective is destroy both visible tumors and unseen circulating cancer cells (micro-metastases). Unfortunately, dosing drugs IV delivers only a small amount with a low concentration at the tumor site. This approach especially for late stage cancers is not highly effective and often quite toxic to the patient. Attempts at direct intratumoral injection with chemotherapeutic agents have not shown the ability to treat the injected tumor, non-injected tumors or micro-metastases. This lack of efficacy for local administration is due possibly to poor dispersion and a lack of cell uptake of the agents. Due to the use of the novel cell penetration enhancing agent INT230-6 treatment demonstrates strong efficacy in animals having large tumors. The Sponsor's in vivo, non-clinical data shows that INT230-6 thoroughly saturates and kills injected tumors. In addition, the drug induces an adaptive (T-cell mediated) immune response that attacks not only the injected tumor, but non-injected tumors and unseen micro-metastases. Cured animals become permanently immunized against the type of cancer that INT230-6 eliminates. Clinical trial IT-01 seeks to determine the safety and potential efficacy of dosing INT230-6 directly into several different types of cancers. In addition animal studies showed a strong synergy of INT230-6 with immune modulation agents. Thus as part of study IT-01 the Sponsor seeks to understand the safety and efficacy of INT230-6 when administered in combination with immuno-therapeutic agents such as antibodies that target Programmed Cell Death (PD-1 or anti-PD-1) and Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4 or anti-CTLA-4) receptors. This study seeks to understand whether tumor regression can be achieved and patient outcomes improved.
Inclusion and Exclusion Criteria
- Inclusion Criteria: INT230-6 monotherapy Cohorts EC2 and EC3, combination with Keytruda cohort DEC2 and combination with Yervoy cohort FEC. Where criteria diverge the DEC2 and FEC specific criteria will be noted.
- The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
- Men and Women > 18 years of age on the day of signing consent.
- For cohort EC2: Have an Eastern Cooperative Oncology Group (ECOG) performance status < or = 2; for cohort DEC and FEC < or equal to 1.
- Includes subjects with loco-regional disease that have relapsed/recurred within 6 months of chemo-radiation and who have no standard of care.
- Includes subjects with metastatic disease who must have failed approved standard therapies that have a clinically significant survival benefit. Failure of all approved therapies that have a modest or marginal impact on survival is not required as long as the treating physician believes that treatment on study is appropriate for the subject and documents that the subject elects to defer the approved therapies. Note: There is no limit on the number of prior therapies that a patient (subject) may have received prior to enrollment in any cohort.
- Subjects must have measurable disease by RECIST 1.1 criteria including one target tumor for injection. Superficial tumors must have one tumor greater than or equal to 1.0 cm, deep tumors greater than or equal to 1.0 cm (as measured by caliper (for non-injected tumors only) or image guidance).
- Subjects must have a minimum of one injectable lesion as determined by the investigator (for superficial tumors) or radiologist (deep tumors); Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- 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 weeks washout is acceptable prior to treatment).and all adverse events have either returned to baseline or stabilized; note: subjects who have received prior platinum therapy are eligible irrespective of their response.
- Prior systemic radiation therapy (either IV, intrahepatic or oral) completed at least 4 weeks prior to study drug administration.
- Prior focal radiotherapy completed at least 2 weeks prior to study drug administration.
- Prior major treatment-related surgery completed at least 4 weeks prior to study drug administration.
- No prior primary or metastatic brain or meningeal tumors unless clinically and radiographically stable as well as off steroid therapy for at least 2 months.
- Life expectancy ≥8 weeks.
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP)
- A WOCBP Subjects who may become pregnant or who are sexually active with a partner who could become pregnant agree to use an effective form of barrier contraception during the study and for at least 60 days in monotherapy (for the pembrolizumab combination please see cohort DEC and for the ipilimumab combination see cohort FEC for the pregnancy criteria) for female subjects. (Male subjects must agree to use contraception during the study for 180 days after administration of study drug).
- Have adequate organ function as defined by the below screening laboratory values that must meet the following criteria:
- WBC ≥2000/μL (≥2 x 10^9/L)
- Neutrophils ≥1000/μL (≥1 x 10^9/L); For DEC combination ≥2000/μL (≥2 x 10^9/L); for FEC combination (≥1500/μL (≥1 x 10^9/L)
- For subjects with planned superficial only injections PT, aPTT, and INR ≤1.5 × ULN Platelets ≥70x103/μL (≥ 70 x 109/L); Hemoglobin ≥8 g/dL (≥80 g/L) (superficial tumor dosing only).
- Creatinine within the institution's laboratory upper limit of normal or calculated creatinine clearance >50 ml/min
- ALT (SGOT)/AST (SGPT) ≤2.5 x ULN without, and ≤ 5 x ULN with hepatic metastases
- Bilirubin ≤2 x ULN (except subjects with Gilbert's syndrome, who must have total bilirubin <3.0 mg/dL (<52 µmol/L); For DEC and FEC cohort combinations ≤1.5 x ULN.
- For subjects with planned deep tumor injections: PT, aPPT, and INR within normal limits; Platelet count ≥100,000/μL; hemoglobin ≥ 9 gm/dL. Note: ALT (SGPT) =alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) =aspartate aminotransferase (serum glutamic oxaloacetic transaminase); ULN=upper limit of normal. 1 Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks. Additional Inclusion Criteria for DEC2 cohort (anti-PD1 combination, Keytruda (pembrolizumab)) Population: Subjects with histologically or cytologically confirmed advanced or metastatic Pancreatic, Cholangiocarcinoma, non-MSI-H and/or MMR proficient colorectal cancer, and Squamous Cell Carcinoma tumors. Additional Inclusion Criteria for FEC cohort (anti-CTLA-4 combination, Yervoy (ipilimumab)) Population: Subjects with histologically or cytologically confirmed advanced or metastatic Hepatocellular carcinoma (HCC), breast cancer regardless of histology (BC) or soft tissue sarcoma NOTE: There are Additional Inclusion Criteria for the combination arms - refer to Investigative site for details. Exclusion Criteria: For INT230-6 Monotherapy cohort EC2, EC3, cohort DEC2-Keytruda combination and cohort FEC-Yervoy combination Subjects who exhibit any of the following conditions at screening will not be eligible for admission into the study: DEC or FEC cohorts have additional criteria.
- History of severe hypersensitivity reactions to cisplatin or vinblastine or other products of the same class.
- Other prior malignancy, except for adequately treated basal or squamous cell skin cancer or superficial bladder cancer, or any other cancer from which the subject has been disease-free for at least 5 years.
- Underlying medical condition that, in the Principal Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events.
- Concurrent medical condition requiring the use of immunosuppressive medications, or systemic corticosteroids; 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 subject is on a stable dose. Non-absorbed intra-articular steroid injections will be permitted; or use of other investigational drugs (drugs not marketed for any indication) within 30 days prior to study drug administration. Use of steroids as prophylactic treatment for subjects with contrast allergies to diagnostic imaging contrast dyes will be permitted.
- For deep tumor cohorts, subjects who require uninterrupted anticoagulants of any type, on daily aspirin therapy or NSAIAs. NOTE: There are Additional Exclusion Criteria for combination arms - please refer to Investigative site for details. Pregnancy Exclusion: A WOCBP who has a positive urine pregnancy test (e.g. within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Please contact the trial administrator to learn more about where you can participate in this trial. Please use the contact form on the right side.