S1404: A Phase III Randomized Trial Comparing Physician/Patient Choice of Either High Dose Interferon or Ipilimumab to MK-3475 (Pembrolizumab) in Patients with High Risk Resected Melanoma.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cancer Trials Ireland

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Jul 2017 → ongoing

Decision date (initial)

2024-10-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516881-12-00

EudraCT number

2016-005197-35

ClinicalTrials.gov

NCT02506153

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Therapy, Efficacy, Pharmacodynamic

a. To compare overall survival (OS) of patients with resected Stage III and IV
melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab versus MK-3475 (pembrolizumab).
b. Among patients who are PD-L1 positive, to compare OS of patients with resected
Stage III and IV melanoma treated with physician/patient choice of either high dose
interferon alfa-2b or ipilimumab versus MK-3475 (pembrolizumab).
c. To compare relapse-free survival (RFS) of patients with resected Stage III and IV
melanoma treated with physician/patient choice.

Secondary objectives 3

1. a. To estimate OS and RFS for patients who are PD-L1 negative or PD-L1 indeterminate in this population. b. To compare OS and RFS of patients between the two arms within PD-L1 positive and negative subgroups and to look at the interaction between PD-L1 (positive versus negative) and treatment arm. c. To assess the safety and tolerability of the regimens.
2. a. To bank tissue and whole blood in anticipation of future correlative studies. b. To evaluate PD-L1 expression through immunohistochemistry assay. c. To evaluate the effect of treatment-related side effects that may have an impact on the health-related domains of quality of life. d. Pharmacokinetic and anti-drug antibody (ADA) testing will be performed on all patients receiving MK-3475 (pembrolizumab).
3. Translational Objectives: a. Evaluate the association between TCRβ variable gene (TRBV) haplotype and Grade 3-4 immune-related adverse events among Stage III melanoma patients treated with adjuvant Ipilimumab or Pembrolizumab. b. Describe the TRBV haplotype distribution.

Conditions and MedDRA coding

High risk resected melanoma.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 22

1. Step 1 Registration: Disease Related Criteria: Patients must have completely resected melanoma of cutaneous origin or of unknown primary. Patients must be classified as Stage IIIA (N2a), IIIB, IIIC, or Stage IV melanoma. Patients with non-ulcerated T1b N1a disease are not eligible. Patients with melanoma of mucosal or other non-cutaneous origin are eligible. Patients with melanoma of ocular origin are not eligible. Patients with a history of brain metastases are ineligible.
2. Step 1 Registration: Disease Related Criteria: Patients are eligible for this trial either at initial presentation of their melanoma or at the time of the first detected nodal, satellite/in-transit, distant metastases, or recurrent disease in prior lymphadenectomy basin or distant site. Nodal, satellite/in-transit metastasis, distant metastases or disease in a prior complete lymphadenectomy basin must have been confirmed histologically by H & E stained slides.
3. Step 1 Registration: Disease Related Criteria: Patients with multiple regional nodal basin involvement are eligible. Gross or microscopic extracapsular nodal extension is permitted.
4. Step 1 Registration: Disease Related Criteria: Patients at initial presentation of melanoma must undergo an adequate wide excision of the primary lesion, if present. Patients with previously diagnosed melanoma must have had all current disease resected with pathologically negative margins and must have no evidence of disease at the primary site or must undergo re-resection of the primary site. A full lymphadenectomy is required for all node-positive patients including those with positive sentinel nodes. Patients with recurrent disease who have had a prior complete lymphadenectomy fulfill this requirement as long as all recurrent disease has been resected. For all patients, all disease must have been resected with negative pathological margins and no clinical, radiologic, or pathological evidence of any incompletely resected melanoma. Patients must be registered within 98 days of the last surgery performed to render the patient free of disease.
5. Step 1 Registration: Specimen Submission Criteria: Patients must have available and be willing to submit a minimum of 5 unstained slides from primary, lymph node, or metastatic site to determine PD-L1 expression.
6. Step 1 Registration: Specimen Submission Criteria: Patients must be offered the opportunity to participate in specimen banking.
7. Step 1 Registration: Specimen Submission Criteria: Patients must be willing to have blood draws for PK/ADA ( MK-3475 arm).
8. Step 1 Registration: Prior/Concurrent Therapy Criteria: Patients may have received prior radiation therapy, including after the surgical resection. All AEs associated with prior surgery and radiation therapy must have resolved to ≤ Grade 1 prior to registration.
9. Step 1 Registration: Clinical/Laboratory Criteria: Patients must be ≥ 18 years of age.
10. Step 1 Registration: Clinical/Laboratory Criteria: All patients must have disease-free status documented by a complete physical examination and imaging studies within 42 days prior to registration. Refer to protocol for imaging requirements.
11. Step 1 Registration: Clinical/Laboratory Criteria: All patients must have a CT or MRI of the brain within 90 days prior to registration (with intravenous contrast (unless contraindicated)).
12. Step 1 Registration: Clinical/Laboratory Criteria: Adequate bone marrow function as evidenced by all of the following: ANC ≥ 1,500 mcL; platelets ≥ 100,000/mcL; Hemoglobin ≥ 10 g/dL.
13. Step 1 Registration: Clinical/Laboratory Criteria: Adequate hepatic function as evidenced by the following: total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (except Gilbert’s Syndrome, who must have a total bilirubin < 3.0 mg/dL), and SGOT (AST) and SGPT (ALT) and alkaline phosphatase ≤ 2 x IULN.
14. Step 1 Registration: Clinical/Laboratory Criteria: Adequate renal function as evidenced by ONE of the following: serum creatinine ≤ IULN OR measured or calculated creatinine clearance ≥ 60 mL/min.
15. Step 1 Registration: Clinical/Laboratory Criteria: LDH performed within 42 days prior to registration.
16. Step 1 Registration: Clinical/Laboratory Criteria: Zubrod Performance Status ≤ 1.
17. Step 1 Registration: Clinical/Laboratory Criteria: A baseline ECG performed within 42 days of registration that is normal or considered not clinically significant.
18. Step 1 Registration: Clinical/Laboratory Criteria: Patients known to be HIV positive are eligible if they meet the following criteria within 30 days prior to registration: stable and adequate CD4 counts (≥ 350 mm3), and serum HIV viral load of < 25,000 IU/ml. Patients may be on or off anti-viral therapy so long as they meet the CD4 count criteria.
19. Step 1 Registration: Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to registration. Women/men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study through 120 days after the last dose of study medication.
20. Step 1 Registration: Patients who are able to complete questionnaires in English, Spanish or French must participate in the quality of life assessments. (Those patients who cannot complete the quality of life questionnaires can be registered to S1404.
21. Step 2 Registration (Randomization): Women of childbearing potential must plan to have a urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
22. Step 2 Registration (Randomization): Patients who are known to have a change in eligibility status after Step 1 registration are not eligible for Step 2 registration.

Exclusion criteria 9

1. Step 1 Registration: Prior/Concurrent Therapy Criteria: Patients must not have received neoadjuvant treatment for their melanoma. Patients must not have had prior immunotherapy including, but not limited to ipilimumab, interferon alfa-2b, high dose IL-2, PEG-IFN, anti-PD-1, anti-PD-L1 intra-tumoral or vaccine therapies. Patients must not be planning to receive any of the prohibited therapies listed in protocol Section 7.2 during the screening or treatment phases of the study.
2. Step 1 Registration: Clinical/Laboratory Criteria: No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, lobular carcinoma of the breast in situ, atypical melanocytic hyperplasia or melanoma in situ, adequately treated Stage I or II cancer (including multiple primary melanomas) from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years.
3. Step 1 Registration: Prior/Concurrent Therapy Criteria: Patients must not be planning to receive concomitant other biologic therapy, radiation therapy, hormonal therapy, other chemotherapy, surgery or other therapy after Step 2 registration.
4. Step 1 Registration: Clinical/Laboratory Criteria: Patients must not have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
5. Step 1 Registration: Clinical/Laboratory Criteria: Patients must not have an active infection requiring systemic therapy.
6. Step 1 Registration: Clinical/Laboratory Criteria: Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
7. Step 1 Registration: Clinical/Laboratory Criteria: Patients must not have received live vaccines within 42 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
8. Step 1 Registration: Clinical/Laboratory Criteria: Patients must not have known active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection prior to registration.
9. Step 1 Registration: Clinical/Laboratory Criteria: Patients must not have a history or current evidence of any condition, therapy or laboratory abnormality that might confound the trial results, interfere with the patient's participation for the full duration of the trial, or indicate that participation in the trial is not in the patient's best interests, in the opinion of the treating investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Progression/Relapse
2. Relapse-Free Survival
3. Overall Survival
4. Performance Status

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cancer Trials Ireland

Sponsor organisation

Cancer Trials Ireland

Address

Rcsi House, 121 Saint Stephen's Green 121 Saint Stephen's Green

City

Dublin 2

Postcode

D02 H903

Country

Ireland

Scientific contact point

Organisation

Cancer Trials Ireland

Contact name

Head of Operations

Public contact point

Organisation

Cancer Trials Ireland

Contact name

Head of Operations

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications