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A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6 (IT-01)

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ClinicalTrials.gov Identifier: NCT03058289
Recruitment Status : Recruiting
First Posted : February 20, 2017
Last Update Posted : November 21, 2018
Sponsor:
Collaborators:
University of Southern California
University Health Network, Toronto
Information provided by (Responsible Party):
Intensity Therapeutics, Inc.

Tracking Information
First Submitted Date  ICMJE February 10, 2017
First Posted Date  ICMJE February 20, 2017
Last Update Posted Date November 21, 2018
Actual Study Start Date  ICMJE February 9, 2017
Estimated Primary Completion Date July 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 15, 2017)
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 3 years ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03058289 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 15, 2017)
  • 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 18 months ]
    Assess the preliminary efficacy of INT230-6 by measuring the length, width and height (centimeters) of injected tumor during the dosing and afterward.
  • Determine pharmacokinetic parameter Peak Plasma (Cmax in ng/mL) of each of the 3 main components of INT230-6. [ Time Frame: Up to 5 months ]
    Characterize the peak plasma profile for the three INT230-6 components after single and then multiple IT tumor site injections for safety purposes.
  • 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 5 months ]
    Characterize the pharmacokinetic AUC profile of each of the three INT230-6 components for AUC after single IT tumor site injection for safety purposes.
  • Key pharmacokinetic parameters, half live (hours) of each of the 3 main components of INT230-6. [ Time Frame: Up to 5 months. ]
    Characterize the half life of each of the three INT230-6 components after single and multiple IT tumor site injections for safety purposes.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 15, 2017)
  • Exploratory: Control or Regression of Non Injected Tumors by Measurement of Length (in centimeters) Radio-graphically Using Computer Tomography or Magnetic Resonance Imaging. [ Time Frame: Up to 18 months ]
    Characterize response in non-injected lesions (up to 5) using length (cm) as the key parameter for measurement.
  • Exploratory: Blood, Genetic and Tissue Biomarker Identification from cell flow phenotyping, tissue analysis, genetic SNP analysis. [ Time Frame: Up to 2 months ]
    Evaluate various tumor and anti-tumor immune response biomarkers from blood, tumor tissue that may correlate with tumor response. Flow panels include Live-Dead, CD3, CD4, CD8, FoxP3, Ki-67, ICOS, PD-1, LAG-3, TIM-3, CTLA-4. and analysis of blood serum cytokine such as Th1/Th2, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and TNF-α.
  • Exploratory: Overall Subject Outcome [ Time Frame: Up to 3 years ]
    Evaluate overall response by RECIST 1.1 including survival
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6
Official Title  ICMJE A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in Adult Subjects With Advanced Refractory Cancers
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 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 will thus seek 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 will seek 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) receptors.

This study seek to understand whether tumor regression can be achieved and patient outcomes improved.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
There are up to 9 cohorts of subjects in the escalation portion of the protocol. The first is a superficial tumor cohort with a low tumor load (1:4 ratio of drug to tumor). The 2nd,3rd and 4th cohorts are in superficial and deep tumors that escalates the total dose and maximal dose per any one tumor. Cohort 5/6/7 will explore a higher drug load (1:2 ratio) and will escalate the total dose and maximal dose per any one tumor. The 8th cohort is reserved for combinations with anti-PD1 agent(s). The 9th optional cohort will be added if a more frequent schedule would be deemed beneficial. The specific regimens of the more frequent dosing regimen cohorts will be designated by the Study Steering Committee.
Masking: None (Open Label)
Masking Description:
There is no masking and all patients will receive INT230-6 treatments.
Primary Purpose: Treatment
Condition  ICMJE
  • Melanoma
  • Head and Neck Cancer
  • Lymphoma
  • Breast Cancer
  • Pancreatic Cancer
  • Liver Cancer
  • Colon Cancer
  • Lung Cancer
  • Glioblastoma
Intervention  ICMJE
  • Drug: INT230-6

    INT230-6 is clear sterile solution administered by injection directly into the tumor to be treated.

    The product contains a cell permeation agent with cisplatin and vinblastine sulfate at fixed concentrations.

    The drug is stored frozen and must be dosed at room temperature.

    Escalation of the drug dose and number of injected tumors is possible in subsequent treatment sessions.

    The drug dose to be administered is set by the tumor volume of the target lesions - not the subject's body surface area

  • Biological: anti-PD-1
    A concomitant anti-PD-1 will be added in cohort D
  • Biological: anti-PD-1 antibody
    A concomitant anti-PD-1 antibody could be added for cohort E
Study Arms  ICMJE
  • Experimental: Cohort A
    INT230-6 injections every 28 days for 5 sessions into only superficial tumors, low starting dose, low concentration per tumor.
    Intervention: Drug: INT230-6
  • Experimental: Cohort B1
    INT230-6 injections every 28 days for 5 sessions into superficial or deep tumors, low starting dose, low drug concentration per tumor
    Intervention: Drug: INT230-6
  • Experimental: Cohort B2
    INT230-6 injections every 28 days for 5 sessions into superficial or deep tumors, medium starting dose, low drug concentration per tumor
    Intervention: Drug: INT230-6
  • Experimental: Cohort B3
    INT230-6 injections every 28 days for 5 sessions into superficial or deep tumors, high starting dose, low drug concentration per tumor
    Intervention: Drug: INT230-6
  • Experimental: Cohort C1
    INT230-6 injections every 28 days for 5 sessions into superficial or deep tumors, low starting dose, high drug concentration per tumor
    Intervention: Drug: INT230-6
  • Experimental: Cohort C2
    INT230-6 injections every 28 days for 5 sessions into superficial or deep tumors, medium starting dose, high drug concentration per tumor
    Intervention: Drug: INT230-6
  • Experimental: Cohort C3
    INT230-6 injections every 28 days for 5 sessions into superficial or deep tumors, high starting dose, high drug concentration per tumor
    Intervention: Drug: INT230-6
  • Experimental: Cohort D
    INT230-6 injections every 28 days for 5 sessions into superficial or deep tumors, dosing per any B or C cohorts (having acceptable tolerability) with addition of anti-PD-1 antibodies
    Interventions:
    • Drug: INT230-6
    • Biological: anti-PD-1
  • Experimental: Cohort E
    INT230-6 injections every 14 days for 5 sessions into superficial or deep tumors treated, dosing per any of A, B, C or D cohorts (having acceptable tolerability) an anti-PD-1 antibody could be added with regimens set by the Study Steering Committee.
    Interventions:
    • Drug: INT230-6
    • Biological: anti-PD-1 antibody
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 15, 2017)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2020
Estimated Primary Completion Date July 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

1. Men and Women > 18 years of age with Eastern Cooperative Oncology Group (ECOG) performance status < 2;

2a. Eligibility: U.S. Sites

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

Includes patients (subjects) with metastatic disease having injections into only superficial lesions that have failed (includes progression, relapse or intolerance) or not be a candidate for approved therapies. Note, patients (subjects) that have approved therapies available, which might confer clinical benefit, may be enrolled as long as the physician properly explains the nature of the treatment, and obtains consent ".

Includes patients (subjects) with metastatic disease having at least one deep tumor injection who have failed (includes progression, relapse or intolerance) all approved lines of therapy prior to enrollment unless they are not an appropriate candidate for a particular approved therapy or no approved therapy exists.

Note: There is no limit on the number of prior therapies that a patient (subject) may have received prior to enrollment in any cohort.

2b. Eligibility: Canadian Sites

Subjects with advanced or metastatic solid tumors that have disease progression after treatment with approved, available therapies (in site's country) for the cancer type or for whom available therapies have limited benefit and the subject refuses the available therapy. Includes subjects with locoregional disease that have relapsed/recurred within 6 months of chemo-radiation; or who have no standard of care or beneficial options. No limit on the number of prior treatments;

3. 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);

4. Subjects must have a minimum of one injectable lesion as determined by the investigator (for superficial tumors) or radiologist (deep tumors).

5. 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 enrollment and all adverse events have either returned to baseline (or resolved to < grade 1); note: subjects who have received prior platinum therapy are eligible irrespective of their response.

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

7. Prior focal radiotherapy completed at least 4 weeks prior to study drug administration.

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

9. 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;

10a. Life expectancy ≥8 weeks all (US); 10b. Life expectancy ≥12 weeks; ≥ 8 weeks superficial tumors (Canada);

11. Subjects who may become pregnant or who are sexually active with a partner who could become pregnant are to use an effective form of barrier contraception during the study and for at least 60 days for female patients and 180 days for male patients after administration of study drug; and

12. Screening laboratory values must meet the following criteria:

  1. White Blood Cell (WBC) ≥2000/μL (≥2 x 10^9/L)
  2. Neutrophils ≥1000/μL (≥1 x 10^9/L)
  3. Platelets ≥70x103/μL (≥ 70 x 10^9/L) (superficial tumor dosing only)
  4. Hemoglobin ≥8 g/dL (≥80 g/L) (superficial tumor dosing only)
  5. Creatinine within the institution's laboratory upper limit of normal (ULN) or calculated creatinine clearance >50 ml/min
  6. alanine aminotransferase /aspartate aminotransferase (ALT/AST) ≤2.5 x ULN without, and ≤ 5 x ULN with hepatic metastases
  7. Bilirubin ≤2 x ULN (except subjects with Gilbert's syndrome, who must have total bilirubin < 3.0 mg/dL (<52 µmol/L))
  8. For patients with planned deep tumor injections: prothrombin time (PT), activated partial thromboplastin time (aPPT), and international normalized ratio (INR) within normal limits; Platelet count ≥100,000/μL; hemoglobin ≥ 9 gm/dL.

    13. Additional criteria for cohort D (anti-PD1 combo) will be supplied in an appendix at a later date.

    Exclusion Criteria:

    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 or topical corticosteroids; systemic or topical corticosteroids must be discontinued at least 4 weeks prior to enrollment. 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, patients who require uninterrupted anticoagulants of any type, on daily aspirin therapy, or NSAIAs.
    6. U.S. ONLY: For all Cohorts, patients who refuse approved therapy for which they are a suitable candidate are not eligible for enrollment on this trial.
    7. Additional criteria for cohort D (anti-PD1 combo) will be supplied in an appendix at a later date.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jeanne Lewis 860-815-7185 jlewis@ce3inc.com
Contact: Karen Du 203-221-1290 KDu@intensitytherapeutics.com
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03058289
Other Study ID Numbers  ICMJE IT-01
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Intensity Therapeutics, Inc.
Study Sponsor  ICMJE Intensity Therapeutics, Inc.
Collaborators  ICMJE
  • University of Southern California
  • University Health Network, Toronto
Investigators  ICMJE
Study Director: Ian B. Walters, M.D. Intensity Therapeutics
Study Chair: Lillian Siu, M.D., FRCP Princess Margaret Hospital, Canada
Principal Investigator: Anthony El-Khoueiry, M.D. USC Norris and HOAG sites
Principal Investigator: Anthony J. Olszanski, M.D., RPh Fox Chase Cancer Center
Principal Investigator: Nilofer Azad, M.D. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Principal Investigator: Giles F Whalen, M.D. UMASS Memorial Medical Group
PRS Account Intensity Therapeutics, Inc.
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP