Nivolumab and HPV-16 Vaccination in Patients With HPV-16 Positive Incurable Solid Tumors

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if nivolumab combined with ISA101 can help to control cancer that has spread. The safety of the study drugs will also be studied. This is an investigational study. ISA101 is not FDA approved or commercially available. It is currently being used for research purposes only. Nivolumab is FDA approved to treat certain types of melanoma in patients who no longer respond to other drugs. Combining ISA101 with nivolumab is investigational. The study doctor can explain how the study drugs are designed to work. Up to 28 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description
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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.

Official Title
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Phase II Trial of Nivolumab and HPV-16 Vaccination in Patients With HPV-16-Positive Incurable Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Biological: ISA 101
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. 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. 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. 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). 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. 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: 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. 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. 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. 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. 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. 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. 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 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ISA101 + Nivolumab<br>HPV-16 vaccination (ISA 101) administered subcutaneously at 100 mcg for a total of 3 doses at 3 to 4 weeks intervals starting on Day 1. Nivolumab administered intravenously at 3 mg/kg every 2 weeks beginning on day 8 after the first vaccine dose. There are 3 weeks in Cycle 1 and 2 weeks in Cycles 2 and beyond. | Biological: ISA 101<br>* 100 mcg administered subcutaneously for a total of 3 doses at 3 to 4 weeks intervals starting on Day 1.<br>Drug: Nivolumab<br>* 3 mg/kg administered by vein every 2 weeks beginning on Day 8 after the first vaccine dose.<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Response Rate (ORR) | ORR defined as sum of subjects with a complete response (CR) and partial response (PR) divided by number of evaluable subjects at 11 weeks from start of treatment. RECIST 1.1 criteria used for assessment. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From the time of the first protocol-specific intervention, every 6 weeks until progression, death, withdrawal of consent or study completion, an average of 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival (PFS) | PFS is defined as the time from first day of treatment to the date of the first documented tumor progression or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST V1.1). RECIST V1.1 defines progression as at least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm. Additionally, the appearance of one or more new lesions is also considered progression. Progression Free survival will be summarized using the method of Kaplan and Meier and Cox proportional hazards model. | From the time of the first protocol-specific intervention, every 6 weeks until progression, death, withdrawal of consent or study completion, an average of 4.5 years. | 
| Progression Free Survival (PFS) Rates at 2 and 3 Years | PFS is defined as the time from first day of treatment to the date of the first documented tumor progression or death due to any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST V1.1). RECIST V1.1 defines progression as at least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm. Additionally, the appearance of one or more new lesions is also considered progression. Progression Free survival will be summarized using the method of Kaplan and Meier and Cox proportional hazards model. | From the time of the first protocol-specific intervention, every 6 weeks until progression, death, withdrawal of consent or study completion, an average of 3 years. | 
| Median Overall Survival | OS is defined as the time from treatment to the date of death, whichever comes first. Overall survival will be summarized using the method of Kaplan and Meier) and Cox proportional hazards model. | 3 years | 
| Overall Survival (OS) Rates at 2 and 3 Years | OS is defined as the time from treatment to the date of death. Overall survival will be summarized using the method of Kaplan and Meier) and Cox proportional hazards model. | up to 3 years | 
| Number of Participants With Adverse Events | The safety and tolerability which will be measured by the incidence of adverse events, serious adverse events, deaths, and laboratory abnormalities. Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject or clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. Laboratory abnormalities are Any laboratory test result that is clinically significant or meets the definition of an SAE, laboratory abnormality that required the subject to have study drug discontinued or interrupted, laboratory abnormality that required the subject to receive specific corrective therapy. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. | at baseline, and continuously throughout the study at the beginning of each subsequent cycle, up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumors, HPV-16 Positive Incurable Solid Tumors, ISA101, HPV-16 vaccination, Nivolumab, BMS-936558, Opdivo