| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously untreated unresectable or metastatic non-small cell lung cancer (NSCLC), or recurrent PD-X refractory NSCLC or recurrent or metastatic squamous head and neck cancer (HNSCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-small cell lung cancer (NSCLC) or head and neck squamous cell cancer (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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10029515 |
| E.1.2 | Term | Non-small cell lung cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 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 response rate of eftilagimod alpha in combination with pembrolizumab in patients with advanced, metastatic, recurrent NSCLC and HNSCC |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of eftilagimod alpha when combined with pembrolizumab
To further evaluate the antitumor activity of eftilagimod alpha when combined with pembrolizumab
To assess the pharmacokinetic and immunogenic properties of eftilagimod alpha |
|
| 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.
2.1 Part A (1st line, PD-X naïve in metastatic setting NSCLC): histologically- or cytologically confirmed diagnosis of non-small cell lung carcinoma stage IIIB not amenable to curative treatment or stage IV not amenable to EGFR/ALK based therapy, treatment naïve for systemic therapy given for advanced/metastatic disease (previous palliative radiotherapy for advanced/metastatic disease acceptable).
Part B (2nd line, PD-X refractory NSCLC): histologically- or cytologically-confirmed diagnosis of NSCLC after failure of first-line treatment (for metastatic/advanced disease) with at least 2 cycles of any PD-1/PD-L1 containing based therapy (e.g. nivolumab, pembrolizumab, avelumab, durvalumab, etc.) alone, or in combination with any other immunotherapeutic or chemotherapy given as part of first-line treatment.
Part C (2nd line PD-X naive HNSCC): 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 after failure of prior platinum-based therapy.
3. Availability of formalin-fixed diagnostic tumor tissue (in the case of participants having received adjuvant therapy, the tissue should be taken after completion of this therapy)
4. Female or male ≥18 years of age on the day of signing the informed consent.
5. All female patients of childbearing potential must have a negative highly sensitive pregnancy test at screening (within 72 hours prior to cycle 1 day 1); all patients of reproductive potential must agree to use highly effective method for contraception from study entry until at least 4 months after the last administration of any study treatment.
A woman must either be,
• 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
•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).
6. A man who is sexually active and has not had a vasectomy must agree to use a barrier method of birth control e.g., either condom or partner with occlusive cap (diaphragm or cervical/vault caps) from study entry until at least 4 months after the last administration of study treatment. All men must also not donate sperm from time of study entry until at least 4 months after the last administration of study treatment.
7. ECOG performance status 0-1.
8. Expected survival > 3 months.
9. Evidence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 modified for immune-based therapeutics (iRECIST). Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
10. Laboratory criteria (collected ≤ 10 days prior to cycle 1 day 1):
• Absolute neutrophil count > 1.5 x 109 /L
• Platelet count ≥ 100 x 109 /L
• Hemoglobin ≥ 9 g/dL or 5.58 mmol/L1
• Serum creatinine ≤ 1.5 × ULN or if > 1.5 ULN with a clearance of ≥ 50 mL/min acc to. GaultCockcroft formula
• Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN for patients with total bilirubin > 1.5 x ULN
• AST (=SGOT) and ALT (=SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases are present.
• International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN unless patient 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 |
1.1 Part A (1st line, PD-X naïve in metastatic setting NSCLC):
NSCLC can be treated with curative intent with either surgical resection and/or chemoradiation and/or radiation.
Has received systemic therapy for the treatment of their stage IV NSCLC. Completion of treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of metastatic disease.
EGFR-sensitizing mutation and/or is echinoderm microtubule-associated protein-like 4(EML4) gene/anaplastic lymphoma kinase (ALK) gene fusion positive (ALK translocation).
- Has received lung radiation therapy that is >30Gy within 6 months of the first dose of trial treatment.
Part B (2nd line, PD-X refractory NSCLC):
Symptomatic ascites or pleural effusion.
>1 line of any systemic anticancer therapy for advanced or metastatic disease.
- Has received lung radiation therapy that is >30Gy within 6 months of the first dose of trial treatment.
Part C (2nd line PD-X naive HNSCC):
Disease is suitable for local therapy administered with curative intent.
Previously treated with > 1 systemic regimen for recurrent and/or metastatic disease.
2. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) (Part A and C only)
3. 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 coinhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher irAE (Part B only)
4. No tumor specimen evaluable for PD-L1 expression by the central study laboratory.
5.1 Prior anti LAG-3 therapy.
6. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue.
7. Prior targeted small molecule therapy, or radiation therapy within 2 weeks prior to cycle 1 day 1
8.1 Has received prior chemotherapy, anti-cancer monoclonal antibody, major surgery, another systemic cancer therapy or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to cycle 1 day 1.
9. Known active CNS metastasis and/or carcinomatous meningitis. Patients 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.
10. Women who are pregnant or lactating. A woman of child-bearing potential who has a positive serum pregnancy test (within 72 hours) prior to cycle 1 day 1.
11. Serious intercurrent infection within 4 weeks prior to cycle 1 day 1 or active acute or chronic infection.
12.1 Evidence of severe or uncontrolled cardiac disease within 6 months prior to first dose of study treatment.
13. Has interstitial lung disease or history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
14. 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.
15. Has a known history of HIV infection.
16.1 Has a known history of Hepatitis B ((defined as a known Hepatitis B surface antigen [HBsAg] positive result) or known active Hepatitis C virus (defined as a known positive anti-Hepatitis C antibody result and known detectable level of HCV RNA [qualitative] on PCR)) infection.
17. Has a life-threatening illness unrelated to cancer.
18. Has previous malignancies within the last three years other than described in inclusion criterion 2, except successfully treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, ductal carcinoma in situ of the breast, and in situ carcinoma of the cervix.
19. 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 autoimmune disease.
20.1 Has a hypersensitivity to eftilagimod alpha and/or pembrolizumab and/or any of its excipients.
21. Live vaccine within 30 days of planned cycle 1 day 1.
Please refer to the protocol for the full exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To determine best overall response rate (ORR) according to iRECIST |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| All efficacy analyses will be based on Investigator's assessment according to iRECIST. Overall response rate (ORR) will be summarized for each part A to C separately by binomial response rate with two-sided 95% exact confidence intervals. using the Clopper-Pearson method. The DOR (based on iRECIST) will be summarized using the Kaplan-Meier product-limit method. The median time to event will be calculated along with 95% CIs using the Kaplan-Meier method. In addition, the proportion of responders still in response at different timepoints will be assessed based on a Kaplan-Meier Plot. Please refer to protocol study assessment. |
|
| E.5.2 | Secondary end point(s) |
Safety profile in terms of frequency, severity and duration of Adverse events (AEs), serious adverse events (SAEs) according to the current NCI CTCAE V5.0, events of clinical interest (ECI) and abnormalities in vital signs, physical examination, 12-lead ECG and safety laboratory and urine assessments
To assess time to and duration of responses according to iRECIST and RECIST 1.1
To assess the response rate according to RECIST 1.1
To assess the disease control rate according to iRECIST and RECIST 1.1
To assess progression free survival (PFS) and overall survival (OS)
To assess occurrence and nature of anti-eftilagimod alpha-specific antibodies
To assess the plasma concentration time profile and derived PK parameters which may include but will be not limited to area under the curve (AUC), peak plasma concentration (Cmax), time to reach Cmax (tmax), systemic clearance (CL), elimination half-life (t1/2) and volume of distribution (VD) of eftilagimod alpha. Please refer to protocol study assessment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The time-to-event endpoints (PFS (based on iRECIST), OS) will be summarized using the Kaplan-Meier product-limit method. The median time to event will be calculated along with 95% CIs using the Kaplan-Meier method. The PFS and OS rate at 3, 6, 12, 18 and 24 months and corresponding 95 % confidence intervals will be estimated using the Kaplan-Meier method. |
|
| 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 | 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| 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
|
| last patient had the EOT visit or 24 months after last patient was recruited, whichever occurs later. |
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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