Clinical Trials /

A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6

NCT03058289

Description:

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 (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.

Related Conditions:
  • Colorectal Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6
  • Official Title: A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in Adult Subjects With Advanced Refractory Cancers

Clinical Trial IDs

  • ORG STUDY ID: IT-01
  • NCT ID: NCT03058289

Conditions

  • Melanoma
  • Head and Neck Cancer
  • Lymphoma
  • Breast Cancer
  • Pancreatic Cancer
  • Liver Cancer
  • Colon Cancer
  • Lung Cancer
  • Glioblastoma
  • Bile Duct Cancer
  • Ovarian Cancer
  • Sarcoma
  • Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
INT230-6Cohort A
anti-PD-1 antibodypembrolizumab, Keytruda, MK-3475Cohort DEC
anti-CTLA-4 antibodyCohort FEC

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort AExperimentalINT230-6 injections every 28 days for 5 sessions into only superficial tumors, low starting dose, low concentration per tumor.
  • INT230-6
Cohort BExperimentalINT230-6 injections every 28 days for 5 sessions into deep tumors, low starting dose, low drug concentration per tumor
  • INT230-6
Cohort EAExperimentalINT230-6 injections every 2 weeks for 5 sessions into superficial tumors, medium starting dose, low drug concentration per tumor
  • INT230-6
Cohort ECExperimentalINT230-6 injections every 2 weeks for 5 sessions into superficial or deep tumors, moderately high starting dose, high drug concentration per tumor
  • INT230-6
Cohort EC2ExperimentalINT230-6 injections every 2 weeks for 5 sessions into superficial or deep tumors, high starting dose, moderate drug concentration per tumor, higher number of tumors to be treated per session than EC
  • INT230-6
Cohort DECExperimentalINT230-6 injections every 2 weeks for 5 sessions with the possibility for INT230-6 retreatment into superficial or deep tumors, with addition of anti-PD-1 antibody Keytruda (pembrolizumab) dosed concurrently starting at Day 1 for two years for selected cancers
  • INT230-6
  • anti-PD-1 antibody
Cohort FECExperimentalINT230-6 injections every 2 weeks for 5 sessions with the possibility for INT230-6 retreatment into superficial or deep tumors, with addition of anti-CTLA-4 antibody dosed concurrently for selected cancers; the final regimen to be set by the study steering committee upon the selection of the CTLA-4 antibody
  • INT230-6
  • anti-CTLA-4 antibody

Eligibility 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.

          1. The participant (or legally acceptable representative if applicable) provides written
             informed consent for the trial.

          2. Men and Women > 18 years of age on the day of signing consent.

          3. For cohort EC2: Have an Eastern Cooperative Oncology Group (ECOG) performance status <
             or = 2; for cohort DEC: <2

          4. Includes subjects with loco-regional disease that have relapsed/recurred within 6
             months of chemo-radiation and who have no standard of care.

          5. 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.

          6. 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).

          7. 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.

          8. 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.

          9. Prior systemic radiation therapy (either IV, intrahepatic or oral) completed at least
             4 weeks prior to study drug administration.

         10. Prior focal radiotherapy completed at least 2 weeks prior to study drug
             administration.

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

         12. 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.

         13. Life expectancy ≥8 weeks.

         14. A female participant is eligible to participate if she is not pregnant, not
             breastfeeding, and at least one of the following conditions applies:

               1. Not a woman of childbearing potential (WOCBP)

               2. 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).

         15. Have adequate organ function as defined by the below screening laboratory values that
             must meet the following criteria:

               1. WBC ≥2000/μL (≥2 x 10^9/L)

               2. Neutrophils ≥1000/μL (≥1 x 109/L); For DEC combination ≥2000/μL (≥2 x 109/L)

               3. 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).

               4. Creatinine within the institution's laboratory upper limit of normal or
                  calculated creatinine clearance >50 ml/min

               5. ALT (SGOT)/AST (SGPT) ≤2.5 x ULN without, and ≤ 5 x ULN with hepatic metastases

               6. 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.

               7. 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.

        3. A female participant is eligible to participate if she is not pregnant, not
        breastfeeding, and at least one of the following conditions applies:

          1. Not a woman of childbearing potential (WOCBP)

          2. 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.

          1. History of severe hypersensitivity reactions to cisplatin or vinblastine or other
             products of the same class.

          2. 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.

          3. 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.

          4. 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.

          5. For deep tumor cohorts, subjects who require uninterrupted anticoagulants of any type,
             on daily aspirin therapy or NSAIAs.

          6. 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

          1. 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).

          2. 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.

          3. 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.

          4. 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

          5. 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

          6. 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.

          7. 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.

          8. 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.

          9. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.

         10. 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.

         11. Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

         12. Has an active infection requiring systemic therapy.

         13. 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.

         14. 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.

         15. 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

         16. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate and severity of treatment-emergent adverse events ≥ grade 3 attributed to study drug using the NCI Common Terminology Criteria for Adverse Events (CTCAE v.4.03) (Scale 1 to 5)
Time Frame:Up to 5 years
Safety Issue:
Description:The primary objective is to assess the safety and tolerability of single and multiple intratumoral doses of INT230-6 in subjects with advanced or recurrent malignancies. This will be assessed by the rate of ≥ grade 3 AE's attributed to INT230-6 and not the underlying disease. All recorded adverse events will be listed and tabulated by system organ class, preferred term, and dose and coded according to the most current version of MedDRA. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance. Adverse Events will be summarized for all reported data and by study period: a) up to and including 28 days post last dose of initial treatment, and b) from first dose of re-initiation of treatment, for subjects who re-initiate study therapy while in follow-up, up to 28 days post-dose of the last re-treatment dose.

Secondary Outcome Measures

Measure:Preliminary Efficacy: Control or Regression of Injected Tumors by Measurement of Length, Width and Height (in centimeters) Radio-graphically Using Computer Tomography or Magnetic Resonance Imaging to Calculate Tumor Volumes (cubic centimeters) Over Time.
Time Frame:Up to 5 years
Safety Issue:
Description:Assess the preliminary efficacy of INT230-6 by measuring the length, width and height (centimeters) of injected tumor during the dosing and afterward.
Measure:Determine pharmacokinetic parameter Peak Plasma (Cmax in ng/mL) of each of the 3 main components of INT230-6.
Time Frame:Up to 4 years
Safety Issue:
Description:Characterize the peak plasma profile for the three INT230-6 components after single and then multiple IT tumor site injections for safety purposes.
Measure:Determine key pharmacokinetic parameter, Area Under the Curve (AUC) (ng*hr/mL) of each of the 3 main components of INT230-6.
Time Frame:Up to 4 years
Safety Issue:
Description:Characterize the pharmacokinetic AUC profile of each of the three INT230-6 components for AUC after single IT tumor site injection for safety purposes.
Measure:Key pharmacokinetic parameters, half live (hours) of each of the 3 main components of INT230-6.
Time Frame:Up to 4 years
Safety Issue:
Description:Characterize the half life of each of the three INT230-6 components after single and multiple IT tumor site injections for safety purposes.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Intensity Therapeutics, Inc.

Trial Keywords

  • Neoplasm
  • Malignancy
  • Intratumoral
  • Intralesional
  • anti-PD-1 antibodies
  • Immuno therapy
  • Dose escalation
  • Platinum
  • Intensity Therapeutics
  • INT230-6
  • Cisplatin
  • Vinblastine
  • PD-1
  • Vinca
  • Keytruda
  • Pembrolizumab
  • CTLA-4
  • Carcinoma

Last Updated