| 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 of 26 patients.
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.
3. Willing and able to comply with site visits and study-related procedures and requirements.
4. Histologically confirmed recurrent or metastatic HPV16-positive Oropharyngeal Cancer (OPC)*. Patients with squamous cell carcinoma 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.
* Recurrent or metastatic disease in the context of this study if defined as recurrent, metastatic or advanced disease.
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 (PCR or in situ hybridization (ISH) 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 total dose of 600 mg of pembrolizumab or 960 mg of nivolumab or equivalent anti-PD-1 antibody with or without chemotherapy for only 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). Prior treatment regimens must have included platrinum- based chemotherapy, 5-fluorouacil (5-FU) or an alternative fluoroparimidine, and cetuximab, if appropriate. Anti PD-1 therapy (as 1st or 2nd line for recurrent/metastatic HPV16 positive OPC) should have been the last treatment regimen that the patient received before entry into the current trial.
7. Prescreening consent only: ability to provide archived tumor sample (preferably tumor block or otherwise at least 10 unstained slides) to allow determination of HPV16-positive status by the central laboratory -or a local laboratory if applicable- 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 upper limit of normal (ULN) and etimated 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 or creatinine clearance (CrCl) > 30 mL/min (using the 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
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. Invasive surgery (defined as surgical intervention requiring general or spinal anesthesia and hospital admission) within 4 weeks prior to start
of study treatment.
2. Patients who, after progressing on anti-PD-1, received additional anticancer therapy (chemotherapy, radiotherapy, experimental TKI's, immunotherapy, anti-EGFR antibodies, surgery). The following palliative treatments are allowed:
- palliative radiotherapy (but NOT for target lesions)
- 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 have permanently discontinued anti-cancer immune modulating therapies due to drug-related toxicity.
4. 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 (with or without continued adjuvant hormonal therapy), 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.
5. Any condition that requires ongoing/continuous corticosteroid therapy (> 10 mg prednisone/day or anti-inflammatory equivalent) within 1 week prior to the first dose of study therapy. Patients who require a brief course of steroids (up to 2 days in the week before enrollment) or physiologic replacement are not excluded.
6. Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. The following are not exclusionary: vitiligo, resolved childhood asthma , endocrinopathies that require only hormone replacement, or psoriasis that does not require systemic treatment.
7. Subjects with known brain metastases or leptomeningeal metastases.
8. Encephalitis, meningitis, organic brain disease (e.g. Parkinson's disease) or uncontrolled seizures in the year prior to first dose of study
therapy.
9. Known history of, or any evidence of interstitial lung disease, or active, non-infectious pneumonitis (in the past 5 years). A history of radiation pneumonitis in the radiation field is permitted.
10. Has participated in a study of an investigational agent or an investigational device, unless approved by the Sponsor.
11. Prior treatment with therapeutic anti-HPV vaccines including ISA101 or ISA101b. Patients who have received a preventive HPV vaccine are allowed.
12. Grade 1 or greater toxicities attributed to systemic prior anti-cancer therapy other than alopecia, fatigue (NCI CTCAE), radiation dermatitis,
laboratory abnormalities that are not considered clinically significant by the treating physician, before administration of study drug.
13. Uncontrolled infection with HIV, hep B or hep C infection; or diagnosis of immunodeficiency.
allowed
14. Any infection requiring hospitalization or treatment with IV antiinfectives 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. Allogeneic stem cell transplantation, or autologous stem cell transplantation.
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. Clinically significant cardiac disease, including left ventricular ejection fraction < 40%, unstable angina, acute myocardial infarction
within 6 months before Cycle 1 Day 1, NYHA Class III or IV congestive heart failure, and uncontrolled arrhythmia.
22. Member of the clinical site study team or his/her immediate family, unless prior approval granted by the Sponsor.
23. Women with a positive serum hCG pregnancy test at the screening/baseline visit. If positive, pregnancy must be ruled out by a
second sensitive hCG pregnancy test for patient to be eligible. Breastfeeding women are also excluded.
24. WOCBP, 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.
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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 | 7 |
| 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 |
| Israel |
| United Kingdom |
| United States |
| Belgium |
| Czechia |
| France |
| Germany |
| Italy |
| Spain |
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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
|
| The end of study is defined as the date of the last contact of the last patient in the study. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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