Eligibility Details:
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.
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