A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6
NCT ID: NCT03058289
Last Updated: 2025-02-27
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1/PHASE2
111 participants
INTERVENTIONAL
2017-02-09
2023-02-22
Brief Summary
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Detailed Description
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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 demonstrated 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 sought 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 sought to understand whether tumor regression can be achieved, and patient outcomes improved.
Conditions
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Study Design
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NON_RANDOMIZED
SEQUENTIAL
Completed, non-escalation cohorts include 1) monotherapy INT230-6 cohort (EC3) dosed every two weeks 2) INT230-6 in a combination with pembrolizumab (DEC2) and 3) INT230-6 in combination with ipilimumab (FEC). Other specific regimens or combinations of INT230-6 may be designated by the Study Steering Committee.
TREATMENT
NONE
Study Groups
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Monotherapy With >=40% Total Tumor Burden Dosed (Cohorts A1/B1/EA/EC/EC2/EC3)
Dosing: \>=40% Total Tumor Burden
A1:INT230-6 injections into only superficial tumors, low starting dose, low concentration per tumor.
B1:INT230-6 injections into deep tumors, low starting dose, low drug concentration per tumor
Dosing schedule for A1 and B1 is every 28 days for 5 sessions
EA:INT230-6 injections into superficial tumors, medium starting dose, low drug concentration per tumor
EC:INT230-6 injections into superficial or deep tumors, moderately high starting dose, high drug concentration per tumor
EC2:INT230-6 injections into superficial or deep tumors, high starting dose, moderate drug concentration per tumor, higher number of tumors to be treated per session than EC.
EC3:INT230-6 injections at fixed maximal dose into superficial or deep tumors, unlimited number of tumors to be treated per session with retreatment once every 9 weeks for two years.
Dosing schedule for EA, EC, EC2 and EC3 is every 2 weeks for 5 sessions
Completed Cohorts
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.
Monotherapy With <40% Total Tumor Burden Dosed (Cohorts A1/B1/EA/EC/EC2/EC3)
Dosing: \<40% Total Tumor Burden
A1:INT230-6 injections into only superficial tumors, low starting dose, low concentration per tumor.
B1:INT230-6 injections into deep tumors, low starting dose, low drug concentration per tumor
Dosing schedule for A1 and B1 is every 28 days for 5 sessions
EA:INT230-6 injections into superficial tumors, medium starting dose, low drug concentration per tumor
EC:INT230-6 injections into superficial or deep tumors, moderately high starting dose, high drug concentration per tumor
EC2:INT230-6 injections into superficial or deep tumors, high starting dose, moderate drug concentration per tumor, higher number of tumors to be treated per session than EC.
EC3:INT230-6 injections at fixed maximal dose into superficial or deep tumors, unlimited number of tumors to be treated per session with retreatment once every 9 weeks for two years.
Dosing schedule for EA, EC, EC2 and EC3 is every 2 weeks for 5 sessions
Completed Cohorts
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.
INT230-6 Combined With Pembrolizumab (Cohorts DEC/DEC2)
DEC: INT230-6 injections every 2 weeks for 5 sessions with the possibility for INT230-6 retreatment into superficial tumors, with addition of anti-PD-1 antibody KEYTRUDA® (pembrolizumab) dosed concurrently starting at Day 1 every 3 weeks for two years for selected cancer types.
Completed Cohort
DEC2:INT230-6 per the dosing of cohort EC3 combined with KEYTRUDA® (pembrolizumab) dosed per DEC concurrently starting at Day 1 for selected cancers.
Completed Cohort
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.
anti-PD-1 antibody
The anti-PD-1 antibody will be added concomitantly with INT230-6 as noted in cohort DEC and DEC2
INT 230-6 Combined With Ipilimumab (Cohort FEC)
FEC: INT230-6 per the EC3 regimen combined with Yervoy (ipilimumab) dosed concurrently starting at Day 1 every 3 weeks for four treatments for selected cancer types.
Completed Cohort anti-CTLA-4 antibody: The anti-CTLA-4 antibody will be added concomitantly with INT230-6 as noted in cohort FEC.
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.
anti-CTLA-4 antibody
The anti-CTLA-4 antibody will be added concomitantly with INT230-6 as noted in cohort FEC
Interventions
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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.
anti-PD-1 antibody
The anti-PD-1 antibody will be added concomitantly with INT230-6 as noted in cohort DEC and DEC2
anti-CTLA-4 antibody
The anti-CTLA-4 antibody will be added concomitantly with INT230-6 as noted in cohort FEC
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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. Have an Eastern Cooperative Oncology Group (ECOG) performance status \< 2; (for pembrolizumab and ipilimumab combinations please see supplements DEC/DEC2 and FEC for ECOG criteria).
4. Populations: INT230-6 will be injected into deep or superficial tumors for subjects with histologically or cytologically confirmed advanced or metastatic cancers; (for pembrolizumab and ipilimumab combinations please see supplements DEC/DEC2 and FEC for Populations).
5. Includes subjects with loco-regional disease that have relapsed/recurred within 6 months of chemo-radiation and who have no standard of care.
6. Subjects with metastatic disease who have failed one or more approved standard therapies, or have no alternate approved therapy available. 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.
7. Subjects must have measurable disease by iRECIST 1.1 criteria including one target tumor for injection by the local site investigator/radiology. 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). Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
8. Subjects must have a minimum of one injectable lesion as determined by the investigator (for superficial tumors) or radiologist (deep tumors).
9. 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 adverse events have either returned to baseline or stabilized.
Note: Subjects who have received prior platinum therapy are eligible irrespective of their response.
15. 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 subject who may become pregnant or who are sexually active with a partner and who could become pregnant agrees to use an effective form of barrier contraception during the study and for at least 180 days in monotherapy; (for pembrolizumab and ipilimumab combinations please see supplements DEC/DEC2 and FEC for pregnancy criteria). (Male subjects must agree to use contraception and refrain from sperm donation during the study for 180 days after administration of study drug.)
16. Have adequate organ function as defined by the below screening laboratory values that must meet the following criteria:
1. WBC ≥2000/μL (≥2 x 109/L).
2. Neutrophils ≥1000/μL (≥1 x 109/L); (for pembrolizumab and ipilimumab combinations please see supplements DEC/DEC2 and FEC for neutrophil criteria).
3. For subjects with planned superficial only injections: PT, PTT/aPTT, and INR ≤1.5 × ULN, Platelets ≥70x103/μL (≥ 70 x 109/L), Hemoglobin ≥8 g/dL
4. Creatinine within the institution's laboratory upper limit of normal or calculated creatinine clearance \>50 ml/min; (for pembrolizumab combination please see supplements DEC/DEC2 for creatine criteria).
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 pembrolizumab and ipilimumab combinations please see supplements DEC/DEC2 and FEC for bilirubin criteria).
7. For subjects with planned deep tumor injections: PT, PTT/aPPT, and INR within normal limits; Platelet count ≥100,000/μL; hemoglobin ≥ 9 g/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.
17. Additional criteria for combination arms can be found in the appropriate combination protocol supplements. Refer to the Investigative site for details.
Exclusion Criteria
12. Prior major treatment-related surgery completed at least 4 weeks prior to study drug administration.
13. 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.
For INT230-6 Monotherapy cohort 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:
18. History of severe hypersensitivity reactions to cisplatin or vinblastine or other products of the same class.
19. 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 2 years.
20. Subjects with tumors \>15 cm (in longest diameter). Treatment plan for subjects with tumors that are 9 to15 cm must be discussed with and approved by the medical monitor.
21. 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.
22. 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 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.
23. For deep tumor cohorts, subjects who require uninterrupted anticoagulants of any type, on daily aspirin therapy or NSAIAs.
24. Use of other investigational drugs (drugs not marketed for any indication) within 28 days prior to study drug administration.
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
18 Years
ALL
No
Sponsors
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Merck Sharp & Dohme LLC
INDUSTRY
Bristol-Myers Squibb
INDUSTRY
Intensity Therapeutics, Inc.
INDUSTRY
Responsible Party
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Principal Investigators
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Brian Schwartz, M.D.
Role: STUDY_DIRECTOR
Intensity Therapeutics
Lillian Siu, M.D., FRCP
Role: STUDY_CHAIR
Princess Margaret Hospital, Canada
Anthony El-Khoueiry, M.D.
Role: PRINCIPAL_INVESTIGATOR
USC Norris and HOAG sites
Anthony J. Olszanski, M.D., RPh
Role: PRINCIPAL_INVESTIGATOR
Fox Chase Cancer Center
Nilofer Azad, M.D.
Role: PRINCIPAL_INVESTIGATOR
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Giles F Whalen, M.D.
Role: PRINCIPAL_INVESTIGATOR
UMASS Memorial Medical Group
Matthew Ingham, M.D.
Role: PRINCIPAL_INVESTIGATOR
Columbia University
Luis Camacho, M.D.
Role: PRINCIPAL_INVESTIGATOR
Center for Oncology and Blood Disorders
Locations
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USC Norris
Los Angeles, California, United States
USC HOAG
Newport Beach, California, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States
UMASS Memorial Medical Center
Worcester, Massachusetts, United States
Columbia University Medical Center
New York, New York, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
Center for Oncology and Blood Disorders
Houston, Texas, United States
Princess Margaret Cancer Center - University Health Network
Toronto, Ontario, Canada
Countries
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Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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KEYNOTE KN-A10
Identifier Type: OTHER
Identifier Source: secondary_id
CA184-592
Identifier Type: OTHER
Identifier Source: secondary_id
IT-01
Identifier Type: -
Identifier Source: org_study_id
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