| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic head and neck squamous cell carcinoma (HNSCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| unresectable recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) |
|
| 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 | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10071540 |
| E.1.2 | Term | Head and neck cancer 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 |
To evaluate the objective response rate of efti in combination with pembrolizumab in Cohort A and to compare to pembrolizumab alone in Cohort A, overall and also as per stratification factors (e.g. CPS).
To evaluate the objective response rate of efti in combination with pembrolizumab in Cohort B. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate overall survival and further antitumor activity of efti when combined with pembrolizumab in Cohort A and to compare to pembrolizumab alone Cohort A, overall and also as per stratification
factors (e.g. CPS). To evaluate the overall survival and further antitumor activity of efti when combined with pembrolizumab in Cohort B.
• To evaluate the safety and tolerability of efti when combined with pembrolizumab compared to pembrolizumab alone.
• To assess the immunogenic properties of efti when combined with pembrolizumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Willing to give written informed consent and to comply with the protocol.
2. Histologically- or cytologically-confirmed recurrent disease not amenable to curative treatment with local or systemic therapy, or metastatic (disseminated) HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx that is considered incurable by local therapies and to be treated in the first line palliative setting and who are PD-X naïve.
3. Availability of tissue for PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate is not sufficient). A newly obtained biopsy (within 90 days prior to start of trial treatment) is preferred but an archival sample is acceptable.
4. Availability of PD-L1 biomarker result by using the FDA approved Dako standardized diagnostic test (PD-L1 IHC 22C3 pharmDx).
5. Availability of tissue for testing of human papillomavirus (HPV) status for oropharyngeal carcinoma (p16 expression testing). Note: If HPV status was previously tested using this method and result is available, no additional testing in central laboratory is required for this trial.
6. Female or male ≥18 years of age on the day of signing the informed consent.
7. All female subjects of childbearing potential must have a negative highly sensitive pregnancy test at screening (within 72 hours prior to cycle 1 day 1); all subjects of reproductive potential must agree to use highly effective method for contraception from trial entry until at least 4 months after the last administration of any trial treatment.
8. A woman must either be,
a) not of childbearing potential: postmenopausal (≥ 60 years of age, or < 60 years of age and amenorrhoeic for 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression with follicle-stimulating hormone (FSH) above 40 U/L and estradiol below 30 ng/L, or if taking tamoxifen or toremifene, and age < 60 years, then FSH and estradiol in the postmenopausal range), permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy), or otherwise incapable of pregnancy
b) of childbearing potential and practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; male partner sterilization (the vasectomized partner should be the sole partner for that subject).
9. ECOG performance status 0-1.
10. Evidence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
11. Subjects who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization.
Note: Subjects should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of trial intervention. Hepatitis B screening test are not required unless: a) known history of HBV infection; b) mandated by local health authority.
12. Subjects with history of HCV infection are eligible if HCV viral load is undetectable at screening.
13. HIV infected subjects must be on anti-retroviral therapy and have a well-controlled HIV infection/disease defined as:
a) Subjects on ART must have a CD4+ T-cell count >350 cells/mm3 at time of screening
b) Subjects on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening
c) Subjects on ART must have been on stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to cycle 1 day 1
Note: no HIV testing is required unless mandated by local health authority.
14. Laboratory criteria (collected ≤ 10 days prior to cycle 1 day 1):
a) Absolute neutrophil count > 1.5 x 10^9/L
b) Platelet count ≥ 100 x 10^9/L
c) Hemoglobin ≥ 9 g/dL or 5.58 mmol/L
d) Serum creatinine ≤ 1.5 × ULN, or if > 1.5 ULN with a clearance of ≥ 50 mL/min acc. to. Gault-Cockcroft formula
e) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN for subjects with total bilirubin > 1.5 x ULN
Note: subjects with known Gilbert’s syndrome can be enrolled.
f) AST (=SGOT) and ALT (=SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases are present.
g) International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants |
|
| E.4 | Principal exclusion criteria |
1. Disease is suitable for local therapy administered with curative intent.
2. Previously treated with ≥ 1 systemic regimen for recurrent and/or metastatic disease (with the
exception of systemic therapy completed >6 months prior if given as part of multimodal treatment for locally or locoregionally advanced disease).
3. Histologically or cytologically confirmed head and neck carcinoma of any other primary anatomic location in the head and neck not specified in the inclusion criteria including subjects with HNSCC of unknown primary, squamous cell carcinoma originating from skin, or nonsquamous histologies (e.g. nasopharynx, salivary gland or mucosal melanoma).
4. Has progressive disease (PD) within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC or requires chemotherapy based therapeutic regimen
due to e.g., rapidly progressing disease or need of aggressive symptom control.
5. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic Tlymphocyte- associated antigen-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
6. No PD-L1 expression result available by cycle 1 day 1.
7. Prior anti-LAG-3 therapy
8. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue.
9. Prior targeted small molecule therapy , or radiation therapy within 2 weeks prior to cycle 1 day 1.
10. Has received prior chemotherapy, anti-cancer monoclonal antibody, major surgery, another systemic cancer therapy or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to cycle 1 day 1.
11. Known active central nervous system metastasis and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable: i.e. without evidence of progression documented by repeat imaging performed after therapy completed for CNS metastasis and with at least 4 weeks difference, clinically stable and without requirement for steroid treatment for at least 14 days prior to cycle 1 day 1.
12. Pregnant, breastfeeding or expecting to conceive or father children within the projected duration of the trial starting with screening visit. A woman of child-bearing potential who has a positive serum pregnancy test (within 72 hours) prior to cycle 1 day 1.
13. Serious intercurrent infection within 4 weeks prior to cycle 1 day 1 or active acute or chronic infection.
14. Evidence of severe or uncontrolled cardiac disease within 6 months prior to first dose of trial
treatment including: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 5.0 Grade ≥ 2, atrial fibrillation > grade 2 not controlled by a pacemaker, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (NYHA III-IV), cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.
15. Has interstitial lung disease or history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
16. Has 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) is not considered a form of systemic treatment and is allowed.
17. HIV-infected subjects with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
18. Has a life-threatening illness unrelated to cancer.
19. Has had an allogenic tissue/solid organ transplant.
20. Has previous malignancies within the last three years other than described in inclusion criterion 2, except curatively treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, ductal carcinoma in situ of the breast, or in situ carcinoma of the cervix
21. Receives continuous systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days prior to cycle 1 day 1. Inhaled or topical steroids and physiological replacement doses of up to 10 mg daily prednisone equivalents are permitted in the absence of active auto-immune disease.
22. Has a hypersensitivity to efti and/or pembrolizumab and/or any of its excipients.
23. Live vaccine within 30 days of planned cycle 1 day 1.
24. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
25. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate (ORR) according to RECIST1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Upon start of trial treatment, subjects will be followed for ORR, PFS and OS. Radiological assessment will be performed at intervals of 9 weeks until week 36 (i.e. week 9, 18, 27, 36) and every 12 weeks thereafter (week 48, 60, 72,…). OS will be monitored until death, withdrawal of consent, loss to follow up or until the end of the trial, whichever occurs first.
Measurability will be assessed according to RECIST 1.1. Treatment decisions will be made according to iRECIST. |
|
| E.5.2 | Secondary end point(s) |
• Overall survival (OS)
• Objective response rate (ORR) according to iRECIST
• Time to and duration of responses according to iRECIST and RECIST 1.1
• Disease control rate according to iRECIST and RECIST 1.1
• Progression free survival (PFS) according to iRECIST and RECIST 1.1
• Occurrence of anti-efti-specific antibodies
• Safety profile in terms of frequency, severity and duration of Adverse events (AEs) and serious adverse events (SAEs) and events of clinical interest (ECI) and abnormalities in vital signs, physical examination, 12-lead ECG and safety laboratory assessments
• Quality of Life using EORTC QLQ-H&N43 and EORTC QLQ-30 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Subjects will be followed for ORR, PFS and OS. Radiological assessment done at intervals of 9 weeks until week 36 and every 12 weeks thereafter. Measurability will be assessed according to RECIST 1.1.,Treatment decisions according to iRECIST.
EORTC QLQ is to be completed on Day 1 of each cycle and EoT
AEs will be recorded from ICF until 30 days after last trial treatment. SAEs will be recorded from ICF until 90 days after last trial drug treatment. SAEs potentially related to trial drugs will be reported also beyond the 90 days.
Assessment points;
- Anti-efti antibodies in combination arms on D1 of cycle 1,3,5,7,10,14 , on D15C 2, on D19C1
-ECG, physical ex+ safety laboratory assessments w: screening ,Day 1 of each cycle and EoT Vital signs: Screening, all visits until EoT |
|
| 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 | No |
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Cohort A Pembro given according to MA, 1 arm pembro alone, other arm in combination with efti |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Ukraine |
| Australia |
| United Kingdom |
| United States |
| Belgium |
| Denmark |
| Germany |
| Romania |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
The trial is completed 2 years after last subject first visit or after the last subject had the end of treatment
visit whatever occurs first but with a minimum of 12 months after last subject first visit. |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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