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JOURNAL ONKOLOGIE – STUDIE

Safety and Efficacy of VB10.16 and Pembrolizumab in Patients With Head-Neck Squamous Cell Carcinoma

Rekrutierend

NCT-Nummer:
NCT06016920

Studienbeginn:
Dezember 2023

Letztes Update:
07.08.2024

Wirkstoff:
VB10.16, Pembrolizumab

Indikation (Clinical Trials):
Carcinoma, Carcinoma, Squamous Cell, Squamous Cell Carcinoma of Head and Neck

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
Nykode Therapeutics ASA

Collaborator:
Merck Sharp & Dohme LLC

Studienleiter

Åse Bratland, MD, PhD
Principal Investigator
Oslo University Hospital

Kontakt

Studienlocations
(3 von 16)

Alle anzeigen

Studien-Informationen

Detailed Description:

This phase 1/2a, open-label, dose-finding trial is designed to evaluate the safety,

tolerability, immunogenicity, and anti-tumor activity of VB10.16 immunotherapy in

patients with HPV16-positive R/M oropharyngeal HNSCC whose tumors express PDL1 (CPS ≥ 1)

and who are eligible for pembrolizumab monotherapy as standard of care. The trial is

designed to determine the biological optimal dose (BOD) of VB10.16 in combination with a

fixed dose of pembrolizumab based on the totality of data (i.e., safety, tolerability,

anti-tumor activity, and HPV16 E6/E7specific cellular immune response). The trial

consists of 2 consecutive phases with separate patient groups in a seamless trial design:

a dose escalation phase (phase 1) and a dose expansion phase (phase 2a). After completing

48 weeks of combination treatment, patients can either continue pembrolizumab treatment

with 200 mg Q3W administration or change to 400 mg Q6W administration at the discretion

of the investigator and after consultation with the Sponsor.

Ein-/Ausschlusskriterien

Inclusion Criteria:

GENERAL REQUIREMENTS

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. Histologically or cytologically confirmed R/M HNSCC, located in the oropharynx,

considered incurable by local therapy and eligible for monotherapy with

pembrolizumab

3. HPV16 positivity of R/M oropharyngeal HNSCC confirmed by designated central

laboratory

4. PD-L1 positivity (CPS ≥1) using the validated PD-L1 IHC 22C3 pharmDx (DAKO) assay.

5. Primary tumor location in the oropharynx.

6. At least 1 measurable lesion per RECIST 1.1

ORGAN FUNCTION

Overall function:

7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1

Hematological function:

8. Platelets ≥100 × 10^9/L (100,000/µL)

9. Neutrophils (absolute neutrophil count [ANC]) ≥1.5 × 10^9/L (1,500/µL)

10. Hemoglobin ≥5.6 mmol/L (9.0 g/dL)

Hepatic and hemostatic function:

11. Bilirubin (BILI), total ≤1.5 × upper limit of normal (ULN) (except Gilbert syndrome,

then direct BILI ≤2 × ULN) or direct bilirubin ≤ULN for participants with total

bilirubin levels >1.5 × ULN.

12. Aspartate transaminase (AST) ≤ 2.5 × ULN or ≤5 × ULN for a patient with liver

metastases.

13. Alanine transaminase (ALT) ≤ 2.5 × ULN or ≤5 × ULN for a patient with liver

metastases.

14. Alkaline phosphatase ≤ 2.5 × ULN or ≤5 × ULN for a patient with liver metastases.

15. International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × 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.

Renal function:

16. Estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m^2 using the

Cockroft-Gault formula

OTHER TRIAL REQUIREMENTS

17. Female patients of childbearing potential: negative serum pregnancy test (≤72 hours)

18. 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 IB 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.

19. Patients capable of giving informed consent must provide signed and dated written

informed consent prior to initiation of any study-related procedures.

Exclusion Criteria:

HNSCC DISEASE

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

PRIOR, CONCURRENT, OR FUTURE INTERVENTIONS

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 molecule 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 VB10.16 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 VB10.16 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)

18. Has received prior surgery within 4 weeks prior to treatment

19. Any planned major surgery

PRIOR OR CONCURRENT MORBIDITY

Malignancy:

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

Hepatic and hemostatic function:

21. Any current bleeding disorder, active bleeding, or bleeding diathesis

Cardiovascular function:

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 VB10.16 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

Pulmonary function:

26. Has a history of (non-infectious) pneumonitis / interstitial lung disease that

required steroids or has current pneumonitis / interstitial lung disease

Immune system and infectious diseases:

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).

Central nervous system (CNS) function:

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

35. New (≤6 months), progressive and/or symptomatic brain metastases

OTHER

36. Is currently participating in or has participated in a trial of an investigational

agent or device in the R/M setting.

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 the patient's 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

Studien-Rationale

Primary outcome:

1. Phase 1: Dose Escalation: Dose Limiting Toxicities (DLT) (Time Frame - 42 days):
Proportion of patient with Dose Limiting Toxicities (DLTs).

2. Phase 2: Dose Expansion: AEs (Time Frame - 12 months):
Proportion of patients with AEs following treatment initiation by severity grade.

3. Phase 2: Dose Expansion: Discontinuation due to adverse reaction (Time Frame - 12 months):
Proportion of patients who discontinue due to an adverse reaction.

4. Phase 2: Dose Expansion: Objective Response Rate (ORR) (Time Frame - 12 months):
Objective Response Rate (ORR), defined as the proportion of patients who have either confirmed CR or confirmed PR as best overall response per RECIST 1.1.

5. Phase 2: Dose Expansion: Immune response (Time Frame - 12 months):
Change from baseline in HPV16 E6/E7-specific T-cell responses as measured by IFN-γ ELISpot in post-vaccination samples.

6. Phase 1+2: Full trial: Objective Response Rate (ORR) (Time Frame - 12 months):
Objective Response Rate (ORR), defined as the proportion of patients who have either confirmed CR or confirmed PR as best overall response (BOR) per RECIST 1.1.

7. Phase 1+2: Full trial: Objective Response Rate (ORR) (Time Frame - 24 months):
Objective Response Rate (ORR), defined as the proportion of patients who have either confirmed CR or confirmed PR as best overall response per RECIST 1.1.

Secondary outcome:

1. Phase 2: Dose Expansion: Disease control rate (DCR) (Time Frame - 12 months):
Disease control rate (DCR), defined as the proportion of patients who have either confirmed CR, confirmed PR, or SD as BOR according to RECIST 1.1.

2. Phase 2: Dose Expansion: Duration of response (DOR) (Time Frame - 12 months):
Duration of response (DOR), defined as time from the date of first documented response of CR or PR to the date of the first documented progression or death due to any cause.

3. Phase 2: Dose Expansion: Duration of response (DOR) (Time Frame - 24 months):
Duration of response (DOR), defined as time from the date of first documented response of CR or PR to the date of the first documented progression or death due to any cause.

4. Phase 2: Dose Expansion: Duration of complete response (DOCR) (Time Frame - 12 months):
Duration of complete response (DOCR), defined as time from the date of first documented response of CR to the date of the first documented progression or death due to any cause.

5. Phase 2: Dose Expansion: Duration of Disease Control (DODC) (Time Frame - 12 months):
Duration of Disease Control (DODC), defined as time from the date of first documented response of CR, PR or SD to the date of the first documented progression or death due to any cause.

6. Phase 2: Dose Expansion: Time to Response (TTR) (Time Frame - 12 months):
Time to Response (TTR), s defined as the time from VB10.16 treatment start date to the date of first documented response of either confirmed CR or confirmed PR.

7. Phase 2: Dose Expansion: Progression-free survival (PFS) (Time Frame - 12 months):
Progression-free survival (PFS), defined as the time from the VB10.16 treatment start date to the date of the first documented progression or death from any cause, whichever occurs first.

8. Phase 2: Dose Expansion: Progression-free survival (PFS) (Time Frame - 24 months):
Progression-free survival (PFS), defined as the time from the VB10.16 treatment start date to the date of the first documented progression or death from any cause, whichever occurs first.

9. Phase 2: Dose Expansion: Overall Survival (OS) (Time Frame - 12 months):
Overall survival (OS), defined as the time from VB10.16 treatment start date to the date of death from any cause.

10. Phase 2: Dose Expansion: Overall Survival (OS) (Time Frame - 24 months):
Overall survival (OS), defined as the time from VB10.16 treatment start date to the date of death from any cause.

11. Phase 2: Dose Expansion: Proportion of progression-free (Time Frame - 6 months):
Proportion of patients who are progression-free and alive.

12. Phase 2: Dose Expansion: Proportion of progression-free (Time Frame - 12 months):
Proportion of patients who are progression-free and alive.

13. Phase 2: Dose Expansion: Patients alive (Time Frame - 6 months):
Proportion of patients who are alive.

14. Phase 2: Dose Expansion: Patients alive (Time Frame - 12 months):
Proportion of patients who are alive.

15. Phase 1+2: Full Trial: Duration of response (DOR) (Time Frame - 12 months):
Duration of response (DOR), defined as time from the date of first documented response of CR or PR to the date of the first documented progression or death due to any cause.

16. Phase 1+2: Full Trial: Duration of response (DOR) (Time Frame - 24 months):
Duration of response (DOR), defined as time from the date of first documented response of CR or PR to the date of the first documented progression or death due to any cause.

17. Phase 1+2: Full Trial: Progression-free survival (PFS) (Time Frame - 12 months):
Progression-free survival (PFS), defined as the time from the VB10.16 treatment start date to the date of the first documented progression or death from any cause, whichever occurs first.

18. Phase 1+2: Full Trial: Progression-free survival (PFS) (Time Frame - 24 months):
Progression-free survival (PFS), defined as the time from the VB10.16 treatment start date to the date of the first documented progression or death from any cause, whichever occurs first.

19. Phase 1+2: Full Trial: Proportion of progression-free (Time Frame - 12 months):
Proportion of patients who are progression-free and alive.

20. Phase 1+2: Full Trial: Proportion of progression-free (Time Frame - 24 months):
Proportion of patients who are progression-free and alive.

21. Phase 1+2: Full Trial: Overall Survival (OS) (Time Frame - 12 months):
Overall survival (OS), defined as the time from VB10.16 treatment start date to the date of death from any cause.

22. Phase 1+2: Full Trial: Overall Survival (OS) (Time Frame - 24 months):
Overall survival (OS), defined as the time from VB10.16 treatment start date to the date of death from any cause.

23. Phase 1+2: Full Trial: Patients alive (Time Frame - 12 months):
Proportion of patients who are alive.

24. Phase 1+2: Full Trial: Patients alive (Time Frame - 24 months):
Proportion of patients who are alive.

25. Phase 1+2: Full trial: AEs following treatment initiation (Time Frame - 12 months):
Proportion of patients with AEs following treatment initiation by severity grade.

26. Phase 1+2: Full trial: AEs following treatment initiation (Time Frame - 24 months):
Proportion of patients with AEs following treatment initiation by severity grade.

27. Phase 1+2: Full Trial: Discontinuation due to an adverse reaction (Time Frame - 12 months):
Proportion of patients who discontinue due to an adverse reaction.

28. Phase 1+2:Full Trial: Discontinuation due to an adverse reaction (Time Frame - 24 months):
Proportion of patients who discontinue due to an adverse reaction.

29. Phase 1+2: Full Trial: Immune response (Time Frame - 12 months):
Change from baseline in HPV16 E6/E7-specific T-cell responses as measured by IFN-γ ELISpot in post-vaccination samples.

Studien-Arme

  • Experimental: Phase1: Dose Escalation: 3 mg VB10.16 + Pembrolizumab
    3 mg of VB10.16 via i.m. needle-free injections in the deltoid muscles Pembrolizumab will be given as standard of care/ background medication via i.v. infusions
  • Experimental: Phase 1: Dose Escalation: 6 mg VB10.16 + Pembrolizumab
    6 mg of VB10.16 via i.m. needle-free injections in the deltoid muscles and quadriceps or gluteus muscles Pembrolizumab will be given as standard of care/ background medication via i.v. infusions
  • Experimental: Phase 1: Dose Escalation: 9 mg VB10.16 + Pembrolizumab
    9 mg of VB10.16 via i.m. needle-free injections in the deltoid muscles and quadriceps and/or gluteus muscle Pembrolizumab will be given as standard of care/ background medication via i.v. infusions
  • Experimental: Phase 2: Dose Expansion: High dose of VB10.16 + Pembrolizumab
    The highest dose of VB10.16 to be safety-cleared in the escalation phase will be given via i.m. needle-free injections in the deltoid muscles and quadriceps and/or gluteus muscle Pembrolizumab will be given as standard of care/ background medication via i.v. infusions
  • Experimental: Phase 2: Dose Expansion: 3 mg VB10.16 + Pembrolizumab
    3 mg of VB10.16 via i.m. needle-free injections in the deltoid muscles Pembrolizumab will be given as standard of care/ background medication via i.v. infusions

Geprüfte Regime

  • VB10.16:
    Intramuscular (i.m.) administrations of VB10.16 every 3 weeks (Q3W) starting at Week 1/Day 1 during a 12-week induction period, followed by a maintenance period with administrations every 6 weeks (Q6W) from Week 13 until Week 48. A total of up to 10 i.m. administrations will be given. VB10.16 will be administered via Pharma Jet® Stratis 0.5 mL needle free injection system.
  • Pembrolizumab (KEYTRUDA®):
    Pembrolizumab 200 mg intravenous (i.v.) will be given in accordance with the local regulatory-approved label Q3W starting at Week 1/Day 1 for as long as the patient tolerates and continues to have clinical benefit from the treatment based on the patient and investigator's decision, up to a maximum of 35 treatments corresponding to approximately 2 years of treatment. After 48 weeks of treatment patients can continue on 200 mg Q3W or change to 400 mg Q6W at the discretion of the investigator and after consultation with the sponsor. Pembrolizumab will be given by i.v. infusion over 30 minutes.

Quelle: ClinicalTrials.gov


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