Study Drug Administration:
There are 3 weeks in Cycle 1 and 2 weeks in Cycles 2 and beyond.
If you are found to be eligible to take part in this study, you will receive ISA101 by
injection on Day 1 of Cycles 1, 2, and 4. You will be closely watched for the first 3 hours
after each dose in order to check for any allergic reactions. Each time, you will receive 2
injections. One may be in your arm and one in your leg.
You will receive nivolumab by vein over 60 minutes on Day 8 of Cycle 1 and Day 1 of Cycles 2
and beyond.
Study Visits:
On Days 1 and 8 of Cycle 1 and Day 1 of every cycle after that:
- You will have a physical exam.
- Blood (about 4 teaspoons) will be drawn for routine tests.
On Day 1 of Cycle 1 and then 1 time a month after that, if you can become pregnant, blood
(about 1 teaspoon) or urine will be collected for a pregnancy test.
At Week 11 and every 6 weeks after that, you will have a CT scan or MRI to check the status
of the disease.
Additional Research Tests:
Blood (up to 20 teaspoons each time) will be drawn before you begin to receive the study
treatment, before you receive ISA101 at Weeks 3 and 7, before you receive nivolumab at Weeks
9 and 11, then every 12 weeks after that. If the doctor thinks it is needed because of white
blood cell recovery from stored cells, one of the every 12 week blood draws may be done
earlier. These blood samples will be used for biomarker tests and tests of the immune system.
Length of Treatment:
You may take ISA101 for up to 3 doses. You may continue taking nivolumab for as long as the
doctor thinks it is in your best interest. You will no longer be able to take the study drug
if intolerable side effects occur, or if you are unable to follow study directions.
If the disease seems like it has gotten worse, you may decide to continue to receive
nivolumab, if you are still eligible. It is possible the study drug may be working even
though the tumor(s) got larger. However, there are risks of continuing to receive the study
drug because the disease may actually be getting worse. This is described in the side effects
section below.
Your participation on the study will be over after the follow-up.
Follow-up Visits:
At about 30 days and 70 days after the last study drug dose, and then as often as the doctor
decides as needed, the following tests and procedures will be performed:
- You will have a physical exam.
- Blood (about 4 teaspoons) will be drawn for routine tests.
At about 30 days, 70 days, and every 6 weeks after that (if you stop the study drug[s] for
reasons other than the disease getting worse), you will have a CT or MRI scan to check the
status of the disease. If the disease gets worse, these scans will stop.
Every 3 months for up to 3 years after your last study drug dose, you will be asked how you
are doing (either at a visit or by phone). The calls should last about 10 minutes.
Inclusion Criteria:
1. Signed Written Informed Consent: a. Subjects must have signed and dated an IRB/IEC
approved written informed consent form in accordance with regulatory and institutional
guidelines. This must be obtained before the performance of any protocol related
procedures that are not part of normal subject care. b) Subjects must be willing and
able to comply with scheduled visits, treatment schedule, laboratory tests and other
requirements of the study.
2. Target Population: a. Men and women >/= 18 years of age. b. Eastern Cooperative
Oncology Group (ECOG) performance status of </= 1. c. Subjects with histologically- or
cytologically-documented incurable Human Papillomavirus (HPV)-16 positive solid tumors
including oropharyngeal squamous cell carcinoma (OPSCC), cervical, vulvar, vaginal,
anal, penile cancer. Incurable HPV-16 solid tumors are defined as tumors which are not
curable by salvage approaches including resection and/or re-irradiation. HPV-16
serotype will be assessed by Cervista assay.
3. Target Population: Subjects can be treatment naïve for metastatic or incurable locally
advanced HPV-16 positive solid tumors or can have one prior line of treatment.Patients
are eligible upon progression after definitive local treatment (usually concurrent
chemoradiation) if they are not candidates for salvage surgery or re-irradiation.
Patients are also eligible after progression on first line chemotherapy for recurrent
disease.
4. Target Population: d. Subjects must have measurable disease by CT or MRI per RECIST
1.1 criteria; Radiographic Tumor Assessment performed within 28 days of study
inclusion. e. Target lesions may be located in a previously irradiated field if there
is documented (radiographic) disease progression in that site. f. Subject entering the
study will need to consent for mandatory biopsy at study entrance and as an optional
procedure at week 11 and at progression for biomarker evaluation. Biopsy should be
excisional, incisional or core needle. Fine needle aspiration is insufficient. g.
Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to
start.
5. Target Population: h. All baseline laboratory requirements will be assessed and should
be obtained within -14 days of study registration. Screening laboratory values must
meet the following criteria: i) WBCs >/= 2000/uL; ii) Neutrophils >/= 1500/uL; iii)
Platelets >/= 100 x 10^3/uL; iv) Hemoglobin >/= 9.0 g/dL; v) Serum creatinine of </=
1.5 X ULN or creatinine clearance > 40 mL/minute (using Cockcroft/Gault formula).
Female CrCl= (140- age in years) x weight in kg x 0.85 72 x serum creatinine in mg/
dL. Male CrCl= (140- age in years) x weight in kg x 1.00 72 x serum creatinine in mg/
dL; vi) AST </= 1.5X ULN; vii) ALT </= 1.5X ULN; viii) Total bilirubin </= ULN (except
subjects with Gilbert Syndrome who must have total bilirubin <3.0 mg/dl).
6. Age and Reproductive Status: a) Women of childbearing potential (WOCBP) must use
method(s) of contraception for 30 days + 5 half-lives (60 days) of the study drugs.
For a teratogenic study drug and/or when there is insufficient information to assess
teratogenicity (preclinical studies have not been done), a highly effective method(s)
of contraception (failure rate of less than 1% per year) is required. Highly effective
birth control in this study is defined as a double barrier method. Examples include a
condom (with spermicide) in combination with a diaphragm, cervical cap, or
intrauterine device (IUD). The individual methods of contraception should be
determined in consultation with the investigator. b) WOCBP must have a negative serum
or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG)
within 24 hours prior to the start of investigational product.
7. Age and Reproductive Status: c) Women must not be breastfeeding. d) Men who are
sexually active with WOCBP must use any contraceptive method with a failure rate of
less than 1% per year. The investigator shall review contraception methods and the
time period that contraception must be followed. Men that are sexually active with
WOCBP must follow instructions for birth control for a period of 90 days plus the time
required for the investigational drug to undergo 5 half-lives (60 days).
Exclusion Criteria:
1. Target Disease Exceptions: a. Subjects with active CNS metastases are excluded.
Subjects are eligible if CNS metastases are adequately treated and subjects are
neurologically returned to baseline (except for residual signs or symptoms related to
the CNS treatment) for at least 2 weeks prior to enrollment. In addition, subjects
must be either off corticosteroids, or on a stable or decreasing dose of </= 10 mg
daily prednisone (or equivalent) for 2 weeks. b. Subjects with carcinomatous
meningitis.
2. Medical History and Concurrent Diseases: a. Subjects with active, known or suspected
systemic autoimmune disease. Subjects with vitiligo, type I diabetes mellitus,
residual hypothyroidism due to autoimmune thyroiditis only requiring hormone
replacement, or conditions not expected to recur in the absence of an external trigger
are permitted to enroll. b. Subjects with a condition requiring systemic treatment
with either corticosteroids (>10 mg daily prednisone equivalent) or other
immunosuppressive medications within 14 days of start. Inhaled or topical steroids,
and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are
permitted in the absence of active autoimmune disease.
3. Medical History and Concurrent Diseases: c. Prior therapy with anti-PD-1, anti-PD-L1,
anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
d. Subjects with a history of interstitial lung disease. e. Other active malignancy
requiring concurrent intervention. f. Subjects with previous malignancies (except
non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon,
endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a complete
remission was achieved at least 2 years prior to study entry AND no additional therapy
is required during the study period.
4. Medical History and Concurrent Diseases: g. Subjects with toxicities attributed to
prior anti-cancer therapy other than alopecia and fatigue that have not resolved to
grade 1 (NCI CTCAE version 4) or baseline before administration of study drug. h.
Subjects who have not recovered from the effects of major surgery or significant
traumatic injury at least 14 days before the first dose of study treatment. i.
Treatment with any investigational agent within 28 days of first administration of
study treatment.
5. Physical and Laboratory Test Findings: a) Known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). b)
Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
ribonucleic acid (HCV RNA) indicating acute or chronic infection.
6. Allergies and Adverse Drug Reaction: a) History of severe hypersensitivity reactions
to other monoclonal antibodies. b) History of allergy or intolerance (unacceptable
adverse event) to study drugs components.
7. Sex and Reproductive Status: a) WOCBP who are pregnant or breastfeeding. b) Women with
a positive pregnancy test at enrollment or prior to administration of study medication
8. Prohibited Treatments and/or Restricted Therapies: a) Ongoing or planned
administration of anti-cancer therapies other than those specified in this study. b)
Use of corticosteroids or other immunosuppressive medications as per Exclusion
Criteria 2b.
9. Other Exclusion Criteria: a) Any other serious or uncontrolled medical disorder,
active infection, physical exam finding, laboratory finding, altered mental status, or
psychiatric condition that, in the opinion of the investigator, would limit a
subject's ability to comply with the study requirements, substantially increase risk
to the subject, or impact the interpretability of study results. b) Prisoners or
subjects who are involuntarily incarcerated. c) Subjects who are compulsorily detained
for treatment of either a psychiatric or physical (eg, infectious disease) illness.
