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A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in Adult Subjects With Advanced Refractory Cancers

Description

Brief Summary
This 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 (melanoma, head and neck, lymphoma, breast) 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 Description
INT230-6 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 seek to understand whether tumor regression can be achieved and patient outcomes improved.

Phase

N/A

Inclusion and Exclusion Criteria

  • Inclusion Criteria: INT230-6 monotherapy Cohort EC2 and combination with Keytruda cohort DEC. Where criteria diverge the EC2 and DEC 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: <2
  • 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 are agrees 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 supplement DEC 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 109/L); For DEC combination ≥2000/μL (≥2 x 109/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 cohort combination ≤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 DEC cohort (anti-PD1 combination) Participants are eligible to be included in the DEC cohort only if all of the following criteria apply: Populations: Enrollment in cohort DEC shall begin with subjects having any cancer type; however, INT230-6 must be dosed into subjects' superficially palpable tumors. Six such subjects must complete 28 days of the combination therapy. Following determination of acceptable safety by the SSC in the 6 subjects receiving the combination, then injection of INT230-6 into deep or superficial tumors for 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. Note: MSI high is defined as at least 2 allelic shifts occurring among the 5 analyzed microsatellite markers as detected by PCR. MMR deficient is defined as loss of expression of at least 1 of 4 proteins (MLH1, MSH2, MSH6, and/or PMS2). Note: the SSC will review the patient population and integrate information from the monotherapy cohorts to further refine the patient population.
  • 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 are agrees to use an effective form of barrier contraception during the study and for at least 60 days in monotherapy and 180 days after the last dose of study treatment for female subjects. (Male subjects must agree to use contraception during the study for 180 days after administration of study drug). 4. Exclusion Criteria: For INT230-6 Monotherapy cohort EC2 and cohort DEC Keytruda combination Subjects who exhibit any of the following conditions at Screening will not be eligible for admission into the study: See DEC or FEC supplements for additional criteria specific to those cohorts.
  • 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.
  • Additional criteria for combination arms can be found in the appropriate supplements. 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. Additional Exclusion Criteria for DEC cohort (anti-PD1 combination) Prior/Concomitant Therapy
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent (Note for the SCC cohort, subjects may have received one prior therapy course with one of these agents).
  • Has received prior therapy with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher irAE (note for the SCC subjects, the same exclusion applies for prior anti-PD-1, anti-PD-L1, or anti PD L2 agents). Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
  • Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
  • Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. Prior/Concurrent Clinical Study Experience
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Diagnostic assessments
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
  • Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Also, prostate, breast and neuroendocrine tumors that are stable on hormonal treatment for a period of 1 year or more without the need to adjust dose are not excluded.
  • Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
  • Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
  • Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
  • Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
  • Has an active infection requiring systemic therapy.
  • Participants with known human immunodeficiency virus (HIV) and/or history of Hepatitis B or C infections or known to be positive for Hepatitis B antigen (HBsAg)/ Hepatitis B virus (HBV) DNA or Hepatitis C Antibody or RNA. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
  • Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study. Other Exclusions
  • Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study treatment.

Sites

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