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.
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 seeks to understand whether tumor regression can be achieved and patient outcomes
improved.
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.
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.
10. Prior systemic radiation therapy (either IV, intrahepatic or oral) completed at least
4 weeks prior to study drug administration; (for ipilimumab combination please see
supplement FEC exclusion criteria).
11. Prior focal radiotherapy completed at least 2 weeks prior to study drug
administration.
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.
14. Life expectancy ≥8 weeks; (for ipilimumab combination please see supplement FEC
inclusion criteria).
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.
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: DEC and FEC combination cohorts have additional Inclusion Criteria - refer to
the Investigative site for details.
Exclusion Criteria:
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
NOTE: DEC or FEC combination cohorts have additional Exclusion criteria. Refer to the
Investigative site for details.
