VB10.16 Plus Pembrolizumab in First Line r/m HNSCC

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Nykode Therapeutics ASA

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

30 Oct 2023 → ongoing

Decision date (initial)

2023-07-12

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Nykode Therapeutics ASA

External identifiers

EU CT number

2022-503055-26-00

ClinicalTrials.gov

NCT06016920

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Dose response, Efficacy, Pharmacogenetic

Dose Escalation Phase 1: To safety-clear doses ≥3 mg VB10.16 and select the recommended Phase 2 dose (RP2D) for the randomized phase.
Randomized Phase 2: To evaluate the efficacy of VB10.16 when combined with pembrolizumab compared to pembrolizumab alone

Secondary objectives 4

1. Randomization phase 2: To assess safety and tolerability of VB10.16 in combination with pembrolizumab compared to pembrolizumab alone
2. Randomization phase 2: To further evaluate the clinical efficacy of VB10.16 in combination with pembrolizumab compared to pembrolizumab alone
3. Dose Escalation Phase 1: To assess safety and tolerability of VB10.16 in combination with pembrolizumab
4. Dose Escalation Phase 1: To evaluate the immunogenicity of VB10.16 in combination with pembrolizumab

Conditions and MedDRA coding

Unresectable recurrent or metastatic HPV16 (Human Papilloma Virus) positive oropharyngeal Head and Neck Squamous Cell Carcinoma

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. ≥18 years of age (or as per national legal age of trial consent, whichever is higher) at date of signing the informed consent form (ICF).
2. Platelets ≥100 × 109 /L (100,000/μL).
3. Neutrophils (absolute neutrophil count [ANC]) ≥1.5 × 109 /L (1,500/µL).
4. Patients capable of giving informed consent must provide signed and dated written informed consent prior to initiation of any study-related procedures
5. Hemoglobin ≥5.6 mmol/L (9.0 g/dL).
6. Total bilirubin ≤1.5 × upper limit of normal (ULN) (except Gilbert syndrome, then direct bilirubin ≤2 × ULN) or direct bilirubin ≤ULN for a patient with total bilirubin levels >1.5 × ULN
7. Aspartate transaminase (AST) ≤2.5 × ULN or ≤5 × ULN for a patient with liver metastases.
8. Alanine transaminase (ALT) ≤2.5 × ULN or ≤ 5 × ULN for a patient with liver metastases.
9. Alkaline phosphatase ≤2.5 × ULN or ≤5 × ULN for a patient with liver metastases.
10. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless the patient is receiving anticoagulant therapy, in which case PT and partial thromboplastin time (PTT)/activated PTT (aPTT) must be within therapeutic range of intended use of anticoagulants.
11. Estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 using the Cockroft-Gault formula.
12. Female patients of childbearing potential: negative serum pregnancy test (≤72 hours).
13. Female patients of childbearing potential must agree to use highly effective contraception throughout the trial (14 days prior to initiation of treatment for oral contraception), and for at least 120 days (according to the current version of the investigator’s brochure for pembrolizumab) after the last dose of pembrolizumab and up to 6 months after the last dose of VB10.16, whichever comes last. Male patients must agree to use male condoms during intercourse throughout the trial, and up to 3 months after the last dose of VB10.16, and must refrain from sperm donation in the same period. Highly effective forms of contraception include: combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner; or sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the trial drugs). The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (calendar, symptothermal, post ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception.
14. Histologically or cytologically confirmed r/m HNSCC,located in the oropharynx, considered incurable by local therapy and eligible for monotherapy with pembrolizumab.
15. HPV16 positivity of r/m oropharyngeal HNSCC confirmed by designated central laboratory.
16. PD-L1 positivity (CPS ≥1) using the validated PD-L1 IHC 22C3 pharmDx (DAKO) assay.
17. Primary tumor location in the oropharynx.
18. At least 1 measurable lesion per RECIST 1.1.
19. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1
20. Life expectancy of ≥3 months, as determined by Gustave Roussy Immuno (GRIm) score 0-1

Exclusion criteria 40

1. Has disease that is suitable for local therapy with curative intent.
2. Has progressive disease ≤6 months after completion of curatively intended concurrent chemoradiotherapy for locoregionally advanced r/m oropharyngeal HNSCC.
3. Primary tumor site of the oral cavity, hypopharynx, larynx or nasopharynx (any histology)
4. Rapidly progressing disease (e.g., tumor bleeding, uncontrolled tumor pain) in the opinion of the investigator.
5. Has received prior palliative radiotherapy within 2 weeks of start of trial treatment or has a prior history of radiation pneumonitis.
6. Any prior investigational or approved systemic antineoplastic drug or invasive medical device (including ICIs), either as monotherapy or as part of a combination regimen administered in the r/m HNSCC setting.
7. Prior solid organ or tissue transplantation (except corneal transplant)
8. Prior autologous or allogeneic hematopoietic stem cell transplantation (HSCT).
9. Prior chimeric antigen receptor T (CAR-T) cell therapy.
10. Prior therapy with a monoclonal or bispecific antibody or antibody fragment (or other molecules with similar mechanism of action) that engages T-cells.
11. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of trial intervention
12. Administration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine within 30 days prior to trial treatment start.
13. Prior administration with a therapeutic HPV16 vaccine.
14. Patients receiving systemic immunosuppression with immunosuppressive agents such as cyclosporine, azathioprine, methotrexate, or tumor necrosis factor alpha (TNF α) blockers for any concurrent condition.
15. Chronic administration of systemic corticosteroids: prednisone >10 mg daily (or dose equivalent).
16. Administration of G-CSF/GM-CSF or transfusions with red blood cells, platelets, or plasma components ≤2 weeks prior to trial treatment start.
17. 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 (e.g., CTLA-4, OX 40, CD137), including pembrolizumab in the locoregional setting.
18. History of major surgery within 4 weeks prior to the first dose of trial treatment or has not fully recovered from surgery-related effects, healings, or complications to ≤ Grade 1 (per Common Terminology Criteria for Adverse Events). Major surgery is considered as any procedure requiring general anesthesia or inpatient hospitalization. The investigator should consult with the medical monitor if uncertain whether a procedure qualifies as major surgery
19. Any planned major surgery.
20. Past or current malignancy other than inclusion diagnosis, except for: Malignancy treated with curative intent and with no known active disease present and has not received chemotherapy for at least 3 years before screening and felt to be at low risk for recurrence by the treating physician. Adequately treated breast ductal carcinoma in situ without evidence of disease. Adequately treated cervical carcinoma in situ, without evidence of disease. Adequately treated non-melanoma skin cancer without evidence of disease. Adequately treated superficial or in situ carcinoma of the bladder without evidence of disease. Prostatic intraepithelial neoplasia without evidence of prostate cancer..
21. Any current bleeding disorder, active bleeding, or bleeding diathesis.
22. Symptomatic congestive heart failure (Grade III or IV as classified by the New York Heart Association), unstable angina pectoris, or cardiac arrhythmia.
23. History of myocardial infarction ≤6 months prior to planned trial treatment start.
24. Uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg), despite optimal medical management.
25. Any other significant cardiac disease(s) that, in the opinion of the investigator, is/are clinically significant and/or unacceptable.
26. Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.
27. Primary immunodeficiency, other immunosuppressive disorder, and/or other causes of immunosuppression.
28. Has an active autoimmune disease that has required systemic treatment in the 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.
29. Has a known history of human immunodeficiency virus (HIV) infection.
30. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
31. Any active, acute, or chronic infection that is uncontrolled and/or requires systemic treatment.
32. Known allergies, sensitivity, or intolerance to VB10.16 (active substance or to any of the excipients), pembrolizumab (active substance or to any of the excipients), or aminoglycosides (especially kanamycin).
33. Any history of intracerebral arteriovenous malformations, cerebral aneurysm, or stroke.
34. Has known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during trial screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of trial treatment. Accordingly, routine brain MRI at screening is not mandatory for all patients, only for those with previously treated but stable brain metastases
35. New (≤6 months), progressive and/or symptomatic brain metastases.
36. Is currently participating in or has participated in a trial of an investigational agent or device in the r/m HNSCC setting.or to the first dose of trial treatment.
37. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the trial or interfere with participation for the full duration of the trial, such that it is not in the best interest of the patient to participate, in the opinion of the treating investigator.
38. Has a known psychiatric or substance abuse disorder that would interfere with the patient’s ability to cooperate with the requirements of the trial.
39. Has a concomitant medical condition requiring receipt of a therapeutic anticoagulant that, in the opinion of the treating physician, would contraindicate administration of VB10.16 and tumor biopsies.
40. Female patients who are pregnant or breastfeeding.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Dose Escalation Phase 1: Proportion of patients with DLTs (42-day DLT period)
2. Randomized Phase 2: Objective response rate (ORR)
3. Randomized Phase 2: Progression-free survival (PFS)

Secondary endpoints 12

1. Randomized Phase 2: Disease control rate (DCR)
2. Randomized Phase 2: Duration of response (DOR)
3. Randomized Phase 2: Time to response (TTR)
4. Randomized Phase 2: Progression-free survival (PFS) rate at 6, 12 and 24 months
5. Randomized Phase 2: Overall survival (OS)
6. Randomization Phase 2: Overall survival (OS) rate at 6, 12 and 24 months
7. Randomized Phase 2: Restricted mean duration of response (RMDOR) at 6, 12 and 24 months
8. Randomized Phase 2: Proportion of patients who experience 1 or more TEAEs assessed by severity grade and relationship
9. Randomized Phase 2: Proportion of patients who discontinue trial treatment due to a TRAE
10. Dose Escalation Phase 1: Proportion of patients who experience 1 or more treatment-emergent adverse events (TEAEs) assessed by severity grade
11. Dose Escalation Phase 1: Proportion of patients who discontinue trial treatment due to a treatment-related adverse event (TRAE)
12. Dose Escalation Phase 1: Change from baseline in HPV16 E6/E7-specific T-cell responses as measured by IFN-γ ELISpot in post-vaccination samples

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Nykode Therapeutics ASA

Sponsor organisation

Nykode Therapeutics ASA

Address

Gaustadalleen 21

City

Oslo

Postcode

0349

Country

Norway

Scientific contact point

Organisation

Nykode Therapeutics ASA

Contact name

Clinical Trial Manager

Public contact point

Organisation

Nykode Therapeutics ASA

Contact name

Clinical Trial Manager

Third parties 10

Locations

7 EU/EEA countries · 18 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 75 files

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

Application history

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