| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent/metastatic HPV16- positive Oropharyngeal Cancer (OPC) |
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| E.1.1.1 | Medical condition in easily understood language |
| Head and neck cancer with human papilloma virus type 16 infection |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10031098 |
| E.1.2 | Term | Oropharyngeal cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To estimate the clinical benefit of ISA101b plus cemiplimab after progression on prior anti-PD-1 therapy, as assessed by objective response rate (ORR) according to RECIST 1.1. |
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| E.2.2 | Secondary objectives of the trial |
• To characterize the safety profile of ISA101b plus cemiplimab.
• To assess preliminary efficacy of ISA101b plus cemiplimab as measured by multiple criteria.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Correlative biomarkers to treatment response or AEs may be assessed in a substudy in the first 26 patients enrolled in the study.
Correlative biomarkers to treatment response or AEs, such as but not limited to the following:
Blood samples at baseline and during treatment for serum cytokines, whole blood for control of tumor mutation analysis, cell-free nucleic acids in plasma, PBMC characterization with profiles by multichannel fluorescence activated cell sorting (FACS), RNA sequence expression analysis (RNAseq), and HPV and control recall antigen-specific immune responses.
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| E.3 | Principal inclusion criteria |
1. Men and women ≥ 18 years of age.
2. Provide informed consent signed by study patient or legally acceptable representative.
3. Willing and able to comply with site visits and study-related procedures and requirements.
4. Histologically confirmed recurrent or metastatic HPV16-positive OPC. Patients with SCC of occult primary site, presenting with lymph node(s) limited only to the neck, are also eligible. Patients should have HPV16 positivity confirmed before being considered a candidate for this study, see inclusion criteria 5.
5. HPV16 genotyping as determined by a specified central reference laboratory with an established polymerase chain reaction (PCR)-based assay. If local HPV16 genotype assessment has been performed, the patient can be enrolled if the result shows HPV16 positivity. Confirmation of HPV16 positive status will then subsequently have to be performed by the central laboratory.
6. Patients who have received a minimum of 4 doses of pembrolizumab or nivolumab or equivalent anti-PD-1 antibody with or without chemotherapy for 1st or 2nd line recurrent/metastatic HPV16-positive OPC. The last dose of anti-PD-1 must been no more than 6 months prior to enrollment into the trial. Progressive disease (PD) must have been diagnosed during or after anti-PD-1 therapy (but not longer than 6 months after the last dose).
7. Prescreening consent only: ability to provide archived tumor sample (tumor block or at least 10 unstained slides) to allow confirmation of HPV16-positive status by the central laboratory using an investigational use only assay.
8. At least one measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST version 1.1 criteria. Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
10. Adequate organ and bone marrow function documented by:
a. Hemoglobin ≥ 8 g/dL
b. Absolute neutrophil count ≥ 1.0 x 109/L
c. Platelet count ≥ 75 x 109/L
d. Serum creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate > 30 mL/min/1.73m2. A 24-hour urine creatinine collection may substitute for the calculated creatinine clearance to meet eligibility criteria.
e. Adequate hepatic function:
i. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (≤3 x ULN if tumor liver involvement)
ii. Aspartate Aminotransferase (AST) ≤ 2.5 x ULN (≤3 x ULN if tumor liver involvement)
iii. Alanine Aminotransferase (ALT) ≤ 2.5 x ULN (≤3 x ULN if tumor liver involvement)
iv. Alkaline Phosphatase (ALP) ≤ 2.5 x ULN (≤3 x ULN if tumor liver or bone involvement)
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| E.4 | Principal exclusion criteria |
1. Major surgery within 14 days of first administration of enrollment.
2.Patients who, after progressing on anti-PD-1, required/ require additional anti-cancer therapy with curative intent subsequent chemotherapy within the last 4 weeks prior to enrollment in order to control disease. The following palliative treatments are allowed: palliative radiotherapy, palliative chemotherapy, palliative surgery, bone resorptive therapy such as bisphosphonates and denosumab but only if patients have been on stable doses for > 4 weeks prior to first dose of test treatment.
3. Patients who, after progressing on anti-PD-1, required subsequent chemotherapy within the last 4 weeks prior to enrollment in order to control disease.
4. Patients who have permanently discontinued anti-cancer immune modulating therapies due to drug-related toxicity.
5. Another malignancy that is progressing or requires active treatment and/or history of malignancy other than oropharyngeal cancer within 3 years of date of first planned dose of study drug, except:
a. Non-melanoma skin cancer that has undergone potentially curative therapy
b. In situ cervical carcinoma
c. Ductal carcinoma in situ of the breast
d. In-situ prostate cancer with non-detectable prostate specific antigen
e. Any tumor that has been deemed to be effectively treated with definitive local control and the patient is deemed to be in complete remission for at least 2 years prior to randomization, and no additional therapy is required during the study period.
6. Any condition that requires ongoing/continuous corticosteroid therapy within 1 week prior to the first dose of study therapy. Patients who require a brief course of steroids or physiologic replacement are not excluded.
7. Ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. The following are not exclusionary: vitiligo, childhood asthma that has resolved, endocrinopathies that require only hormone replacement, or psoriasis that does not require systemic treatment.
8. Untreated or active primary brain tumor, CNS metastases, leptomeningeal disease or spinal cord compression.
9. Encephalitis, meningitis, organic brain disease (e.g. Parkinson’s disease) or uncontrolled seizures in the year prior to first dose of study therapy.
10. Known history of, or any evidence of interstitial lung disease, or active, non-infectious pneumonitis. A history of radiation pneumonitis in the radiation field is permitted.
11. Has participated in a study of an investigational agent or an investigational device within 4 weeks of first dose of study therapy.
12. Uncontrolled infection with human immunodeficiency virus, hepatitis B or hepatitis C infection; or diagnosis of immunodeficiency.
14. Any infection requiring hospitalization or treatment with IV anti infectives within 2 weeks of first dose of study therapy.
15. Receipt of a live vaccine within 4 weeks of planned start of study drug.
16. Prior allogeneic stem cell transplantation, or autologous stem cell transplantation within 12 weeks of the start of study drug, unless discussed with and approved by the Sponsor.
17. Recipients of organ transplants at any time unless discussed with and approved by the medical monitor.
18. Known allergy or hypersensitivity to components of study drug or excipients.
19. Known psychiatric or substance abuse disorders that would interfere with participation with the requirements of the study.
20. Any medical condition, co-morbidity, physical examination finding, or metabolic dysfunction, or clinical laboratory abnormality that, in the opinion of the investigator, renders the patient unsuitable for participation in a clinical trial due to high safety risks and/or potential to affect interpretation of results of the study.
21. Member of the clinical site study team or his/her immediate family, unless prior approval granted by the Sponsor.
22. Women with a positive serum hCG pregnancy test at the screening/baseline visit. If positive, pregnancy must be ruled out by ultrasound for patient to be eligible. Breastfeeding women are also excluded.
23. Women of childbearing potential, or sexually active men, who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose. Highly effective contraceptive measures include:
a. stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening
b. intrauterine device (IUD); intrauterine hormone releasing system (IUS);
c. bilateral tubal ligation
d. vasectomized partner
e. and/or sexual abstinence
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Objective Response Rate (ORR) based on radiographic response, measured by RECIST version 1.1.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Continuously throughout the study |
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| E.5.2 | Secondary end point(s) |
• Incidence and severity of TEAEs/AESIs/SAEs and ≥3 grade laboratory abnormalities during the treatment period and up to 105 days after the last dose of study treatment.
• Duration of Response (DOR).
• Progression-free Survival (PFS).
• Overall survival (OS) until death, loss to follow-up or termination of the study by the Sponsor.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Continuously throughout the study |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Czechia |
| France |
| Germany |
| Israel |
| Italy |
| Spain |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of study is defined as the date the last patient completes the last study visit, withdraws from the study, or is lost to follow-up (LVLS) |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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