| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HPV16-Positive Platin-Resistant Oropharyngeal Cancer (OPC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Head and neck cancer with human papilloma virus type 16 infection |
|
| 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 | 20.0 |
| 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) |
|
| 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. |
|
| 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 at 12 months will also be compared. |
|
| 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. |
|
| E.3 | Principal inclusion criteria |
1. Males and females, ≥ 18 years of age.
2. Sign and date an IRB/IEC approved written consent form.
4. Diagnosed with histologically confirmed recurrent or metastatic HPV16 positive OPC, not amenable to any therapy with curative intent. Subjects with HPV16 positive squamous cell carcinoma (SCC) of occult primary site, presenting with lymph node(s) in the neck, are also
eligible.
5. HPV16 genotyping determined by polymerase chain reaction (PCR)-based assay. HPV genotyping requires a minimum of 10 unstained formalin-fixed paraffin-embedded (FFPE) slides of tumor sample (archival or recent).
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
7. Tumor progression or recurrence on or after platinum-containing chemotherapy for the treatment of primary, metastatic or recurrent disease, or within 6 months of platinumcontaining chemotherapy administered as part of neo-adjuvant or adjuvant therapy.
8. 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) scanor 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.
9. Fresh tumor tissue must be provided for biomarker correlative studies unless the investigator determines that this could impose a significant risk to the subject. It is recommended to discuss such cases with the Medical Monitor. Tumor lesions used for biopsy should not be lesions used as RECIST target lesion, unless there are no other lesions suitable for biopsy. If a RECIST target lesion is used for biopsy, the lesion must be ≥ 2 cm in longest diameter.
10. 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.
11. Screening laboratory values must meet the following criteria (using National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v5.0) and should be obtained within 14 days prior to randomization:
i) White blood cell count (WBC) ≥ 2 x 109/L
ii) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
iii) Platelets ≥ 100 x 109/L
iv) Hemoglobin ≥ 9.0 g/dL
v) Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl)
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)
If transaminase levels ( [AST] and/or [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 must be ≤ 3 x ULN. Note regarding drug induced liver failure (DiLi): According to Hy's Law of Drug Induced Liver Injury a drug causes hepatocellular injury, generally defined as an elevated ALT or AST by 3-fold or greater above the upper limit of normal, combined with an elevation of serum total bilirubin of greater than 2× the upper limit of normal,without findings of cholestasis (defined as serum alkaline phosphatase activity less than 2× the upper limit of normal).
i) Calcium levels must be normalized and maintained within normal limits for study entry and on treatment. Medical management of calcium levels is permitted.
ii) Subjects with an initial magnesium < 0.5 mmol/L (1.2 mg/dL) may receive
corrective magnesium supplementation but should also continue to receive either prophylactic weekly infusion of magnesium and/or oral magnesium supplementation (e.g., magnesium oxide) at the investigator’s discretion. Levels should be up to 0.5 mmol/L (1.2 mg/dL) or higher before randomization.
12. Subjects must have baseline oxygen saturation by pulse oximetry of ≥ 92% at rest on
room air.
13. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of study drug.
14. Women must not be breastfeeding.
15. 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.
16. 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.
17. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP still must undergo pregnancy testing.
|
|
| E.4 | Principal exclusion criteria |
1. 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. Base of skull involvement without definitive evidence of dural or parenchymal (brain) involvement is acceptable.
2. 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.
3. 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.
4. 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.
5. 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 systemic 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. Inhaled or topical corticosteroids and adrenal replacement doses < 10 mg daily prednisone or equivalent are permitted.
6. Subjects requiring maintenance treatment with immunosuppressive doses of systemic corticosteroids. Subjects being treated with a short course of corticosteroids (> 10 mg/day prednisone equivalents) should discontinue this therapy at least 2 weeks prior to start of study treatment.
7. 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.
8. Prior treatment with therapeutic anti-HPV vaccines including ISA101 or ISA101b. Subjects who have received a preventive HPV vaccine are allowed.
9. 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. Subjects with residual grade 1 toxicities or toxicities attributed to systemic prior anticancer therapy that have become chronic and are not expected to resolve, such as neuropathy after platinum based therapy, can be included in this trial.
10. Invasive surgery (defined as surgical intervention requiring general or spinal anesthesia, and hospital admission) within 28 days prior to start of study treatment.
11. Subjects being treated or requiring treatment with: chemotherapy for cancer, biological therapy for cancer, the PI3-kinase inhibitor idelalisib (ZydeligR), any other investigational therapy, unless five half-lives have elapsed after the last dose within 28 days of first administration of study treatment.
12. Administration of any live vaccine within 30 days before first dose of study drug.
13. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus or
hepatitis C virus, except for:
Subjects with HIV who have controlled infections are permitted.
Subjects with hepatitis B (HepBsAg+) virus who have controlled infection are permitted.
Subjects who are hepatitis C virus antibody positive (HCV Ab +) who have
controlled infection are permitted.
14. Known history of allergy to any of the drug components of ISA101/101b
15. Known history of allergy to any of the drug components of cemiplimab and its excipients.
16. Known history of allergy to tetracycline or doxycycline.
17. History of severe hypersensitivity reaction to any human monoclonal antibody.
19. 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).
20. Subjects with an uncontrolled or significant heart disease such as long QT syndrome with QTcF > 480 ms on baseline ECG, NYHA III/IV or uncontrolled arrhythmia.
21. History of organ transplant, including allogenic peripheral stem cell or bone marrow transplant. |
|
| 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.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Continuously throughout the study |
|
| 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Continuously throughout the study |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| End of study is defined as the date of the last visit of the last subject (LVLS) |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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