| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Cutaneous Squamous Cell Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10077314 |
| E.1.2 | Term | Skin squamous cell carcinoma metastatic |
| 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 |
| The primary objective of this study is to estimate the clinical benefit of cemiplimab monotherapy versus cemiplimab in combination with RP1 for patients with metastatic (nodal or distant) CSCC or with locally advanced CSCC as assessed by ORR according to central review. |
|
| E.2.2 | Secondary objectives of the trial |
•To estimate ORR for patients with locally advanced CSCC
• To estimate ORR for patients with metastatic CSCC
• To estimate ORR according to investigator review
• To estimate ORR for patients having previously received systemic CSCC-directed therapy
• To estimate ORR for patients not having previously received systemic CSCC-directed therapy
• To estimate the duration of response (DOR) by central and investigator review
• To estimate PFS by central and investigator review
• To estimate the complete response (CR) rate by central review and investigator review
• To estimate OS
• To estimate disease-specific survival (DSS)
• To estimate 3 year survival
• To assess the safety and tolerability of cemiplimab alone and combined with RP1
• To assess the change of cemiplimab and cemiplimab combined with RP1 on quality of life using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Voluntary agreement to provide written informed consent and willingness and ability to comply with protocol requirements.
2. Histologically confirmed diagnosis of CSCC that is locally advanced or metastatic.
3. At least 1 lesion that is measurable and injectable by study criteria (tumor of ≥1cm in longest
diameter or ≥1.5 cm in shortest diameter for lymph nodes).
If a previously radiated lesion is to be followed as a target lesion, progression of that lesion
must be confirmed by biopsy after radiation therapy. Previously radiated lesions may be
followed as non-target lesions if there is at least 1 other measurable target lesion.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
5. Male or female ≥18 years old.
6. Hepatic function:
a. Total bilirubin ≤1.5 x upper limit of normal (ULN); (if liver metastases ≤3 x ULN). Patients
with Gilbert’s Disease and total bilirubin up to 3 x ULN may be eligible after
communication with and approval from the medical monitor.
b. Transaminases (ALT or AST) ≤3 x ULN (or ≤5.0 x ULN, if liver metastases)
c. Alkaline phosphatase (ALP) ≤2.5 x ULN (or ≤5.0 x ULN, if liver or bone metastases)
Note for patients with hepatic metastases who wish to enroll: If transaminase levels
(AST and/or ALT) are >3 x but ≤5 x ULN, total bilirubin must be ≤1.5 x ULN. If total bilirubin
is >1.5 x but ≤3 x ULN, both transaminases (AST and ALT) must be ≤3 x ULN.
7. Renal function: Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥30cc/min
8. Bone marrow function:
a. Hemoglobin ≥9.0 g/dL
b. Absolute neutrophil count (ANC) ≥1.5 x 109/L
c. Platelet count ≥100 x 109/L
9. Prothrombin time (PT) ≤ 1.5 x ULN (or international normalization ratio [INR] ≤ 1.3) and
partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN.
10. Anticipated life expectancy >12 weeks.
11. Females of childbearing potential who have a negative serum pregnancy test at screening
and urine on Cycle 1 Day 1 prior to dosing.
12. Female subjects of childbearing potential who are willing to use a highly effective method
of birth control (which must include at least a barrier method) or who are surgically sterile
or abstain from heterosexual activity for the course of the study and for 6 months after last
dose of study drug.
13. Male subjects of reproductive potential who agree to use a highly effective method of
contraception during sexual contact with females of childbearing potential (which must
include at least a barrier method) starting from the first dose of study drug to 6 months after
the last dose of study drug and also agree to abstaining from donating sperm during this
period.
14. Screening electrocardiogram (ECG) without evidence of acute ischemia or prolonged QT
interval > 440ms.
15. Baseline troponin < 0.06 ng/mL.
16. Baseline pulse oximetry with pO2 ≥ 92% on room air.
17. Locally advanced only: Surgery must be deemed contraindicated in the opinion either a
medical oncologist with experience in cutaneous malignancy management or a
dermatologist, or a head and neck surgeon, or multi-disciplinary disease management
team.
18. Locally advanced only: Patients must be deemed as not appropriate for radiation therapy.
This must include the opinion of a radiation oncologist or either a medical oncologist, head
and neck surgeon or dermatologist with expertise in cutaneous malignancies, or a multidisciplinary
team.
19. All patients must consent to provide archived or newly obtained tumor material (either
formalin-fixed, paraffin-embedded [FFPE] block or 20 unstained slides) for central pathology
review and biomarker analyses.
20. Patients must consent to undergo biopsies of a CSCC lesion at screening, Cycle 1 Day 1
(combination arm) and Cycle 2 Day 1 (±3 business days). Other non-mandatory biopsies
may also be taken at completion of treatment, and at other time points that may be clinically
indicated in the opinion of the investigator to aid in determining response status. An archival
FFPE block obtained within 12 months of study start is acceptable as a substitute for the
screening biopsy. |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with an oncolytic therapy.
2. Patients with active significant herpetic infections or prior complications of HSV-1 infection
(e.g. herpetic keratitis or encephalitis).
3. Patients who require intermittent or chronic use of systemic (oral or intravenous) anti-virals
with known anti-herpetic activity (e.g. acyclovir).
4. Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required
treatment with systemic immunosuppressive treatments, which may suggest risk for
immune-related adverse events (irAEs) or has a diagnosis of immunodeficiency disorders
(such as human immunodeficiency virus (HIV) disease or organ transplantation or
hematologic malignancies associated with immune suppression).
Note: the following are not exclusionary: vitiligo, childhood asthma that has resolved, type
1 diabetes, residual hypothyroidism that required only hormone replacement, or psoriasis
that does not require systemic treatment.
5. Prior treatment with an agent that blocks the PD-1/PD-L1 pathway.
6. Prior treatment with other immune modulating agents other than as adjuvant or neoadjuvant
therapy within 3 years. Examples of immune modulating agents include therapeutic anti-cancer vaccines,
cytokine treatments (other than G-CSF or erythropoietin), or agents that target CTLA-4,
4-1BB (CD137), PI 3-K-delta, or OX-40.
7. Untreated brain metastasis(es) that may be considered active.
8. Immunosuppressive corticosteroid doses (> 20 mg prednisone daily or equivalent) within
4 weeks prior to the first dose of cemiplimab.
9. Known infection including active infection with hepatitis B virus (HBV), hepatitis C virus
(HCV) or HIV.
10. History of interstitial lung disease (ILD)/pneumonitis within the last 5 years or a history of
ILD/pneumonitis requiring treatment with systemic steroids.
11. History of myocarditis or congestive heart failure (as defined by the New York Heart
Association Functional Classification III or IV), or unstable angina, serious uncontrolled
cardiac arrhythmia, uncontrolled infection or myocardial infarction within 6 months of dosing.
12. Grade ≥ 3 hypercalcemia at time of enrollment.
13. Any systemic anticancer treatment (chemotherapy, targeted systemic therapy,
photodynamic therapy), investigational or standard of care, within 30 days of the initial
administration of RP1 or cemiplimab or planned to occur during the study period (patients receiving bisphosphonates or denosumab are not excluded), radiation therapy within 14
days of initial administration of cemiplimab or planned to occur during the study period.
14. History of documented allergic reactions or acute hypersensitivity reaction attributed to
antibody treatments.
15. Patients with allergy or hypersensitivity to RP1 or cemiplimab or to any of the excipients
must be excluded. Specifically, because of the presence of trace components in
cemiplimab, patients with allergy or hypersensitivity to doxycycline or tetracycline are
excluded.
16. Patients who are breast feeding.
17. Concurrent malignancy other than CSCC and/or history of malignancy other than CSCC
within 3 years of date of first planned dose of cemiplimab, except for tumors with negligible
risk of metastasis or death. Examples include: adequately treated BCC of the skin,
carcinoma in situ of the cervix, or ductal carcinoma in situ of the breast, or low-risk early
stage prostate adenocarcinoma (T1-T2aN0M0 and Gleason score ≤6 and prostate specific
antigen [PSA] ≤10 ng/mL) for which the management plan is active surveillance, or prostate
adenocarcinoma with biochemical-only recurrence with documented PSA doubling time of
> 12 months for which the management plan is active surveillance (D'Amico 2005, Pham
2016). Patients with hematologic malignancies are excluded, except for patients with
chronic lymphocytic leukemia (CLL) who are considered stable and not on active treatment.
18. Any acute or chronic psychiatric problems that, in the opinion of the investigator, make the
patient ineligible for participation.
19. Any medical 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.
20. Inability to undergo any contrast-enhanced radiologic response assessment.
21. Is currently participating in or has participated in a study of an investigational agent or has
used an investigational device within 4 weeks prior to the first dose of study treatment. Note:
Participants who have entered the follow-up phase of an investigational study may
participate as long as it has been 4 weeks after the last dose of the previous investigational
agent.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint for this study is ORR according to central review:
• RECIST version 1.1 will be used to determine ORR with
the exception that PD must be confirmed by documentation of further progression 4-8 weeks
following the initial assessment of PD.
• In patients suspected of achieving a CR, tumor biopsies may be used in the final
determination of complete versus PR.
Patients who are deemed not evaluable (NE) by RECIST version 1.1 or inevaluable
by the clinical or composite response criteria will be considered as not reaching
PR/CR for ORR. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
RECIST version 1.1 will be used to determine ORR. For the purposes of this study, patients should be re-evaluated for response every 9 weeks. Confirmatory scans should also be obtained 4-8 weeks following initial documentation of objective
response or progressive disease. |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy outcome measures are:
• ORR for patients with metastatic disease
• ORR for patients with locally advanced disease
• ORR by investigator assessments:
− For patients in which all response assessments are performed on radiologic scans
according to RECIST 1.1, the investigator’s response assessment for such patients will
be RECIST 1.1 assessment from radiologic scans.
− For patients in which all response assessments are performed on photographs
according to Clinical Response Criteria (in Appendix 2), the investigator’s response
assessment for such patients will be according to clinical assessments according to
RECIST 1.1.
• ORR for patients having previously received systemic CSCC-directed therapy
• ORR for patients not having previously received systemic CSCC-directed therapy
• Duration of response by investigator and central review
• PFS by investigator and central review
• OS
• DSS
• 3 year survival
• CR rate by investigator and central review
• Change in scores of patient-reported outcomes on EORTC QLQ-C30
• Safety and tolerability of cemiplimab alone and combined with RP1 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
RECIST version 1.1 will be used to determine ORR. For the purposes of this study, patients should be re-evaluated for response every 9 weeks. Confirmatory scans should also be obtained 4-8 weeks following initial documentation of objective
response or progressive disease. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 |
| Australia |
| Canada |
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 28 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 28 |
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