Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000901808
Ethics application status
Approved
Date submitted
25/05/2021
Date registered
12/07/2021
Date last updated
28/07/2022
Date data sharing statement initially provided
12/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase 2 study of neoadjuvant Pembrolizumab in cutaneous squamous cell carcinoma (cSCC).
Scientific title
A phase 2 study of de-escalation in resectable, locally advanced cutaneous squamous cell carcinoma with the use of neoadjuvant Pembrolizumab.
Secondary ID [1] 304314 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 322062 0
Head and Neck Cancer 322063 0
Cutaneous Squamous Cell Cancer 322064 0
Condition category
Condition code
Cancer 319784 319784 0 0
Head and neck

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Initial: Pembrolizumab - 200mg, every three weeks, Intravenous Infusion, 4 cycles

Patients will be assessed for response via medical imaging and this will determine whether patients will undergo surgery plus or minus external beam radiation therapy (XRT).

Patients will be deemed for surgery if they have not had a complete clinical and radiological response (based on physical examination and radiological imaging using PET and/or CT Scan). Surgery will be scheduled for 3 weeks after the 4th cycle of pembrolizumab.
Patients who, at surgery, demonstrate nodal metastases and/or those with greater than 10% viable tumour cells post-resection will receive Post-operative radiotherapy.

Patients who demonstrate a complete clinical and radiological response (based on physical examination and radiological imaging using PET and/or CT Scan), will undergo a series of biopsies to confirm a complete pathological response. Patients will be referred for surgical resection plus or minus radiotherapy if the biopsies do not indicate a complete pathological response.

Patients requiring Radiation therapy will commence 4-6 weeks following surgery. The radiation therapy dose will be 50-66 Gray, 25-33 treatments, 5 days a week for 5-7 weeks in accordance with the Head and Neck Consensus Guidelines. The dose and duration will be determined by the pathological response at surgery.

Post Surgery/Post XRT: Pembrolizumab - 200mg, every three weeks, Intravenous Infusion, 17 cycles.

Patients will attend the day oncology unit at their treating institution for administration of all study therapies as applicable.

The overall duration of pembrolizumab is 87 weeks (4 treatments, given every 3 weeks prior to surgery; 17 treatments, given every three weeks post surgery/radiotherapy).
Intervention code [1] 320658 0
Treatment: Drugs
Intervention code [2] 320659 0
Treatment: Surgery
Intervention code [3] 320660 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 327645 0
Changes in pathological tumour response from baseline to end of 4 cycles of study drug pre-surgery. Response will be determined by review of pathological specimen taken at surgical resection.

Response to the neo-adjuvant treatment will determine whether patient proceeds to surgery alone or surgery plus radiotherapy.
Timepoint [1] 327645 0
As a change from baseline to end of 4th cycle of study drug (12 weeks post-intervention commencement)
Secondary outcome [1] 396072 0
Composite Changes in pathological and/or clinical tumour response from baseline until end of intervention and at relapse of disease. Response will be measured via clinical assessment by clinician, pathological reviews and radiological imaging using PET Scans and CT Scans.
Timepoint [1] 396072 0
Every available time point and as a change from baseline.
Timepoints:
Baseline, Week 7 and Week 15 post-intervention commencement and every 3 months during adjuvant pembrozilumab (total 17 cycles), every 4 months following completion of adjuvant pembro for a maximum of two years and at relapse of disease

Eligibility
Key inclusion criteria
Histologically confirmed diagnosis of invasive cSCC that is locally advanced (Stage II-IV on AJCC 8th edition) assessed preoperatively as sufficiently high risk that they will warrant post-operatively RT who is a candidate for a complete resection.

Participants must have measurable disease based on RECIST 1.1.

Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days prior to the start of treatment.

Participants must have adequate organ function collected within 10 days prior to the start of treatment.

Participants must have a tissue sample adequate for translational research.

Participants must have a life expectancy of greater than 6 months.

Be at least 18 years of age on the day of signing the informed consent.

Female participants: Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of trial medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP) OR
- A WOCBP who agrees to use an adequate method of contraception during the treatment period and for at least 120 days after the last dose of study treatment.

The participant (or legally acceptable representative if applicable) must be willing and able to provide written informed consent for the trial. The participant may also provide consent for Future Biomedical Research. However the participant may participate in the main trial without participating in Future Biomedical Research.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participant has metastatic/ unresectable cSCC that cannot be potentially cured with surgical resection, radiotherapy, or with a combination of surgery and radiotherapy.

Participant has any other histologic type of skin cancer other than invasive squamous cell carcinoma as the primary disease under study, eg, basal cell carcinoma that has not been definitively treated with surgery or radiation, Bowen’s disease, merkel cell carcinoma, melanoma.

Participants with any prior allogeneic solid organ or hematopoietic stem celltransplantations are excluded.

Participant has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).

Participant has received prior systemic anti-cancer therapy including investigational agents for cSCC.

Participant has received prior radiotherapy to the target lesion.

Participant has received a live vaccine within 30 days prior to the first dose of trial drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed-virus vaccines and are allowed; however, intranasal influenza vaccines(eg, FluMist®) are live- attenuated vaccines and are not allowed.

Participant is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of trial treatment.

Ongoing or recent (within 2 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 HIV disease or organ transplantation or hematologic malignancies associated with immune suppression).

Participant has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of trial drug.

Participant has a diagnosis and/or has been treated for additional malignancy within the past 3 years prior to allocation.
- Participants with cSCC of the skin that have undergone potentially curative therapy are not excluded if not related to current diagnosis.
- Participants with basal cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical cancer or melanoma in situ) that have undergone potentially curative therapy are not excluded.
- Participants with low-risk early-stage prostate cancer, defined as below are not excluded: Stage T1c or T2a with a Gleason score 6 or less, and a prostate-specific antigen (PSA) (10 ng/ml or less) either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to trial allocation.

Participant has an active autoimmune disease that has required systemic treatment in the past 2 years (eg, with use of disease-modifying agents, anticoagulants, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.

Participant has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

Participant has an active infection requiring systemic therapy.

Participant has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.

Participant has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.

Participant has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the trial.

Participant is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Pathologic response is the proportion of participants in the analysis population who have a pathological complete response or major pathologic response.

This will be determined independently by two designated pathologist, and in the case of a discrepancy, a third pathologist will be consulted.
Response will be determined as
• Complete pathological response (no viable tumour cells in the surgical resection specimen or no viable tumour cells in those patients who have undergone mapping biopsies for a complete radiological and PET response)
• Major pathological response (less than or equal to 10% viable tumour cells)
• Pathological partial response (11-50% viable tumour cells)
• Pathological stable/progressive disease (greater than 50% viable tumour cells).

The primary endpoint is pathological response rate. The point estimate and 95 percent CI will be provided using exact binomial method proposed by Clopper and Pearson (1934). Participants in the primary analysis population (APaT) without pathological response data will be counted as non-responders

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
4/07/2022
Actual
29/06/2022
Date of last participant enrolment
Anticipated
1/01/2024
Actual
Date of last data collection
Anticipated
6/01/2025
Actual
Sample size
Target
27
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 19551 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 19552 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [3] 19553 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment postcode(s) [1] 34160 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 34161 0
4029 - Herston
Recruitment postcode(s) [3] 34162 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 308689 0
Commercial sector/Industry
Name [1] 308689 0
Merck Sharp and Dohme (MSD)
Country [1] 308689 0
Australia
Primary sponsor type
Government body
Name
Metro South Hospital and Health Services
Address
199 Ipswich Road, Woolloongabba, QLD 4102, Australia
Country
Australia
Secondary sponsor category [1] 309571 0
Commercial sector/Industry
Name [1] 309571 0
Merck Sharp & Dohme (MSD)
Address [1] 309571 0
Level 1 - Building A,
26 Talavera Road
Macquarie Park NSW 2113
Country [1] 309571 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308612 0
Metro South HREC
Ethics committee address [1] 308612 0
Metro South Research
Level 7 Translational Research Institute
37 Kent Street, Woolloongabba, QLD, 4102
Ethics committee country [1] 308612 0
Australia
Date submitted for ethics approval [1] 308612 0
04/10/2021
Approval date [1] 308612 0
10/11/2021
Ethics approval number [1] 308612 0

Summary
Brief summary
The main purpose of this research project is to see if immunotherapy drug pembrolizumab may shrink the tumour prior to surgery and potentially reduce the requirement of subsequent treatment such as post-operative radiotherapy (PORT) in patients with Squamous Cell Carcinoma (SCC) of the skin.

Who is it for?
You may be eligible for this study if you are aged 18 years or older, have a confirmed diagnosis of invasive SCC, and are a candidate for surgical resection and/or post-operative radiotherapy.

Study details
All participants will receive pembrolizumab intravenously once every 3 weeks for a total of 4 cycles prior to planned surgery. Depending on the effect of pembrolizumab, participants will either receive surgery, surgery and PORT, or neither, depending on the proportion of tumour cells seen on biopsy. All participants will subsequently have post-operative pembrolizumab for 12 months in three weekly visits.

Your participation in this research project consists of:
• A screening period of up to 28 days: After you sign this Participant informed consent form, testing will be done to determine if this research project is suitable for you.
• A treatment period of approximately 64 weeks and
• An end of treatment visit, approximately 30 days after the completion of the study drug treatment period. This may be because you have completed the treatment period, or you or your doctor has decided to stop you receiving the study treatment.
• A post-treatment follow-up period of approximately up to 2 years or until your skin cancer returns or the study ends

It is hoped that this study will help us understand whether pembrolizumab can shrink the tumour, in which patients this may be more likely to occur, and any side effects that may be experienced during this study. This may help to treat other patients with SCC of the skin in future and reduce the requirement for surgery or radiotherapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 50334 0
Dr Rahul Ladwa
Address 50334 0
Staff Specialist - Division of Cancer Services
Princess Alexandra Hospital
199 Ipswich Road, Woolloongabba Qld 4102
Country 50334 0
Australia
Phone 50334 0
+61 7 3176 6577
Fax 50334 0
Email 50334 0
[email protected]
Contact person for public queries
Name 50335 0
Dr Rahul Ladwa
Address 50335 0
Staff Specialist - Division of Cancer Services
Princess Alexandra Hospital
199 Ipswich Road, Woolloongabba Qld 4102
Country 50335 0
Australia
Phone 50335 0
+61 7 3176 6577
Fax 50335 0
Email 50335 0
[email protected]
Contact person for scientific queries
Name 50336 0
Dr Rahul Ladwa
Address 50336 0
Staff Specialist - Division of Cancer Services
Princess Alexandra Hospital
199 Ipswich Road, Woolloongabba Qld 4102
Country 50336 0
Australia
Phone 50336 0
+61 7 3176 6577
Fax 50336 0
Email 50336 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All individual data collected during trial in summary
When will data be available (start and end dates)?
immediately following publication, no end date
Available to whom?
Researchers who provide a methodoligically sound proposal on a case by case basis
Available for what types of analyses?
Sub-study, meta-analysis
How or where can data be obtained?
Subject to approval by PI - email: [email protected]


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.