E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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 |
Primary objective: To evaluate if the addition of ISA101b to cemiplimab results in improved overall response rate (ORR) compared to cemiplimab alone, according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by independent review.
Primary Safety Objective: To assess the safety and tolerability of the combination of cemiplimab plus ISA101b compared to placebo plus cemiplimab. |
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E.2.2 | Secondary objectives of the trial |
- Duration of response (DOR) by independent review in subjects randomized to receive ISA101b + cemiplimab compared to placebo + cemiplimab.
- Time to response (TTR) by independent review in subjects randomized to receive ISA101b + cemiplimab compared to placebo + cemiplimab.
- Progression-free survival (PFS) by independent review in subjects randomized to receive ISA101b + cemiplimab compared to placebo + cemiplimab. The PFS rate at 6 months will also be compared.
- Median overall survival (OS) in subjects randomized to receive ISA101b plus cemiplimab compared to placebo + cemiplimab. The OS rate will also be compared. |
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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 |
Biomarker sub study:
Objective: 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. Males and females, ≥ 18 years of age. 2. Willing and able to sign and date an IRB/IEC-approved written informed consent form. 3. Willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study. 4. Subjects with histologically confirmed recurrent or metastatic (in the context of this study, defined as recurrent, metastatic, or advanced disease) HPV16 positive OPC, whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1) and who are candidates for first line therapy with an PD-1 blocking antibody, AND subjects with recurrent or metastatic HPV16 positive OPC with disease progression on or after platinum containing chemotherapy. 5. HPV16 genotyping determined by a specified central reference laboratory with an established polymerase chain reaction (PCR)-based assay. If local HPV specific genotype assessment or in situ hybridization (ISH) assessment has been performed, the subject can be enrolled if the result shows HPV16 positivity. Confirmation of HPV16 positive status will be performed retrospectively by the central laboratory. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 7. Measurable disease, defined as at least 1 lesion that can be accurately measured in at least 1 dimension with a minimum size of 10 mm by computed tomography (CT) scan or magnetic resonance imaging (MRI) per RECIST 1.1 criteria. Indicator lesions must not have been previously treated with surgery, radiation therapy, or radiofrequency ablation, unless there is documented progression after therapy. 8. Fresh tumor tissue is to be provided for biomarker and other correlative studies unless the investigator determines that this could impose a significant medical risk to the subject. It is recommended to discuss such cases with the Medical Monitor. 9. Prior curative radiation therapy must have been completed at least 8 weeks prior to study drug administration. Prior focal palliative radiotherapy must have been completed at least 2 weeks before study drug administration. 10. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization: i) White blood cell count (WBC) ≥ 2x10e9/L ii) Absolute neutrophil count (ANC) ≥ 1.5x10e9/L iii) Platelets ≥ 100x10e9/L iv) Hemoglobin ≥ 8.0 g/dL v) Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl)> 40 mL/min vi) Hepatic function: a. Total bilirubin ≤ 1.5 x ULN (if liver metastases ≤ 3 x ULN). Subjects with Gilbert’s Disease and total bilirubin up to 3 x ULN may be eligible if total bilirubin < 3.0 mg/dL. b. Transaminases (ALT and AST) ≤ 3 x ULN (or ≤ 5.0 x ULN, if liver metastases) c. Alkaline phosphatase ≤ 2.5 x ULN (or ≤ 5.0 x ULN, if liver or bone metastases) Note for subjects with hepatic metastases: If transaminase levels (aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT]) > 3 x but ≤ 5 x ULN, total bilirubin must be ≤ 1.5 x ULN. If total bilirubin > 1.5 x but ≤ 3 x ULN, both transaminases (AST and ALT) must be ≤ 3 x ULN. 11. Subjects must have baseline oxygen saturation by pulse oximetry of ≥ 92% at rest on room air. 12. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drug. 13. Women must not be breastfeeding. 14. WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug(s), and then for 6 months post treatment completion. 15. Males who are sexually active with WOCBP must agree to follow instructions for methods of contraception for the duration of treatment with study drugs, and then for a total of 6 months post treatment completion. 16. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP still must undergo pregnancy testing. |
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E.4 | Principal exclusion criteria |
1. Subjects with previously untreated metastatic or unresectable, recurrent HPV16 positive OPC whose tumors do not express PD-L1 (CPS<1) and who are therefore not candidates for monotherapy with an anti-PD-1 antibody. 2. Subjects with known brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if i) these have been treated, ii) there is no MRI (or CT scan where MRI is contraindicated) evidence of progression for at least 4 weeks after completion of the last treatment, iii) absence of new neurological signs/symptoms, and iv) there is no need for corticosteroid use for management of these lesions. 3. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results. 4. History of other malignancy ≤ 3 years prior to entry into this trial with the exception of basal cell or squamous cell skin carcinoma(s) which were treated with local resection only, OR carcinoma in situ of the cervix, prostate or breast, OR low grade non-muscle invasive superficial bladder cancer (TaLG)/carcinoma in situ of the bladder. 5. Subjects with active, known, diagnosed or suspected auto-immune disease. Subjects suffering from vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring thyroid hormone replacement therapy, or psoriasis not requiring systemic treatment can be enrolled. 6. Patients diagnosed with active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis within the last 5 years, or another condition requiring immunosuppressive doses of medication such as systemic corticosteroids or absorbed topical corticosteroids (doses ≥ 10 mg/day prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration. 7. Subjects requiring maintenance treatment with immunosuppressive doses of systemic corticosteroids. 8. Prior treatment with an anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, cemiplimab), as well as anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways. 9. Prior treatment with more than one chemotherapy regimen for the management of metastatic OPC. 10. Prior treatment with therapeutic anti-HPV vaccines including ISA101 or ISA101b. Subjects who have received a preventive HPV vaccine are allowed. 11. 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. 12. Prior treatment with other immune-modulating agents that was (a) administered within 4 weeks (28 days) prior to the first dose of cemiplimab, OR (b) associated with immune-mediated adverse events that were ≥ Grade 1 within 90 days prior to the first dose of cemiplimab, OR (c) associated with toxicity that resulted in discontinuation of the immune-modulating agent. 13. Invasive surgery (defined as surgical intervention requiring general or spinal anesthesia, and hospital admission) within 28 days prior to start of study treatment. 14. Subjects being treated or requiring treatment with: - chemotherapy, for cancer, - biological therapy for cancer, - the PI3-kinase inhibitor idelalisib (Zydelig®); - any other investigational therapy; unless five half-lives have elapsed after the last dose of the above listed medication. 15. Administration of any live vaccine within 30 days before first dose of study drug. 16. Uncontrolled infection with HIV, hepatitis B or hepatitis C virus, except for subjects with HIV, hep B virus or who are HCV Ab + whose infection is controlled. 17. Known history of allergy to any of the drug components of ISA101/101b: e.g. ISA101/101b, Montanide, or Macrogolglycerol Ricinoleate, also known as cremophore. 18. Known history of allergy to any of the drug components of cemiplimab and its excipients. 19. Known history of allergy to tetracycline or doxycycline. 20. History of severe hypersensitivity reaction to any human monoclonal antibody. 21. Severe concurrent illness(es) including psychiatric conditions that would limit compliance with study requirements. 22. Serious systemic infection requiring hospital treatment with intravenous antibiotics within 14 days prior to start of study treatment (last dose of antibiotic given at least 14 days prior to start of study treatment). 23. Subjects with an uncontrolled significant heart disease such as long QT syndrome with QTcF > 480 ms on baseline ECG, NYHA III/IV or uncontrolled arrhythmia. 24. History of organ transplantion, including allogenic peripheral stem cell or bone marrow transplantion |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint: ORR by independent review in subjects randomized to receive ISA101b plus cemiplimab compared to cemiplimab alone.
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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) |
Safety endpoint: Frequency and severity of toxicity in subjects randomized to receive ISA101b plus cemiplimab compared to cemiplimab alone. |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Brazil |
Mexico |
United States |
France |
Poland |
Netherlands |
Spain |
Czechia |
Germany |
Italy |
Belgium |
Hungary |
United Kingdom |
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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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End of study is defined as the date of the last visit of the last subject (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 | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 22 |