Bevacizumab and Pembrolizumab Combination in Platinum-resistant Recurrent/Metastatic NPC

NCT03813394 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: NP01/2017/MSD3475
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single center, randomized, phase Ib/II open-label study of pembrolizumab (pembro or MK-3475) with or without bevacizumab in patients with recurrent non-curable or metastatic nasopharyngeal carcinoma (NPC).

Conditions

Locally Recurrent Cancer; Metastatic Nasopharyngeal Cancer

Keywords

Immunotherapy; Epstein Barr virus; Nasopharyngeal cancer; Anti-PD1; Tumor neoantigens

Outcome Measures

Primary Outcomes (3)

• Primary endpoint of ORR

  Comparison of the two treatment arms will be evaluated using the Fisher's exact test. The treatment effect will be quantified via the relative risk estimate and its associated 95% confidence interval (CI).

  2 years

• The secondary endpoint of PFS

  This will be summarized using the Kaplan-Meier survival estimate for each group. As an exploratory analysis, the log-rank test will be used for comparing differences in PFS, with its effect quantified based on hazard ratio and its 95% CI.

  2 years

• Progression free survival (PFS)

  This is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded central imaging assessment or death due to any cause, whichever occurs earlier.

  2 years

Study Arms (2)

Treatment Arm A

EXPERIMENTAL

Intravenous pembrolizumab alone,D8 of 21-day cycle.

Drug: pembrolizumab

Treatment Arm B

EXPERIMENTAL

Intravenous pembrolizumab preceded by an infusion of bevacizumab (Day 1 of 21-day cycle).

Drug: pembrolizumab; Drug: bevacizumab

Interventions

pembrolizumab DRUG

-Pembrolizumab in Solution for Injection

Treatment Arm A; Treatment Arm B

bevacizumab DRUG

* Bevacizumab in Concentrate for Solution * Bevacizumab in Concentrate for Solution

Treatment Arm B

Eligibility Criteria

• Age: 21 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- Participants are eligible to be included in the study only if all of the following criteria apply:
• The participant (or legally acceptable representative if applicable) provides written consent for the trial.
• Participants who are at least 21 years of age on the day of signing informed consent with histologically or cytologically confirmed diagnosis of non-keratinizing nasopharyngeal carcinoma (NPC) that has recurred at loco regional and/or distant sites will be enrolled in this study.
• Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Have locally or centrally determined EBV-positive NPC by EBV-encoded small RNA in situ hybridization (EBER in situ hybridization \[ISH\]) assay. If EBV-positive status has been previously determined by EBER ISH assay, then no re-testing is required. Note: If EBV status by EBER ISH assay has not been previously determined, tumor tissue from archival tissue may be submitted for EBV determination.
• Received one or more lines of chemotherapy, which must include prior treatment with a platinum agent and must not be amenable to potentially curative radiotherapy or surgery.
• Have provided archival tumor tissue sample of newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.
• Willingness to donate blood and tissue for mandatory translational research studies.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Have an adequate organ function.Specimens must be collected within 10 days prior to the start of study treatment.
• A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 120 days after the last dose of study medication.
• A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.

You may not qualify if:

• Participants are excluded from the study if any of the following criteria apply:
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization. Note: Participants must have recovered from all AEs to previous therapies to ≤ Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible. Note: If participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to first dose of study treatment.
• Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• Has a condition requiring systemic steroid therapy (\> 10 mg daily prednisone equivalents) or any other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment. Inhaled or topical steroids and adrenal replacement doses \<10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if \< or = 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayedtype hypersensitivity reaction caused by contact allergen) is permitted.
• Has a known history of active TB (Bacillus Tuberculosis).
• Has had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, antiCTLA-4 antibody.
• Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.
• Has hypersensitivity to bevacizumab or any of its components.
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, transitional cell carcinoma of urothelial cancer, or carcinoma in situ (e.g. breast or cervical carcinoma in situ) that have undergone potentially curative therapy are not excluded.
• Has known brain metastases or leptomeningeal metastases, whether treated or untreated. NOTE: Primary nasopharyngeal cancers that directly invade the skull base and extend into the infratemporal fossa (e) are not regarded as brain metastases and are not excluded.
• Has 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, etc) is not considered a form of systemic treatment.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.

Sponsors & Collaborators

• National University Hospital, Singapore: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

National University Hospital

Singapore, Singapore

Location

Related Publications (4)

• Ma BB, Hui EP, Chan AT. Systemic approach to improving treatment outcome in nasopharyngeal carcinoma: current and future directions. Cancer Sci. 2008 Jul;99(7):1311-8. doi: 10.1111/j.1349-7006.2008.00836.x. Epub 2008 May 21.

  PMID: 18498420 BACKGROUND

• Ma BBY, Lim WT, Goh BC, Hui EP, Lo KW, Pettinger A, Foster NR, Riess JW, Agulnik M, Chang AYC, Chopra A, Kish JA, Chung CH, Adkins DR, Cullen KJ, Gitlitz BJ, Lim DW, To KF, Chan KCA, Lo YMD, King AD, Erlichman C, Yin J, Costello BA, Chan ATC. Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742). J Clin Oncol. 2018 May 10;36(14):1412-1418. doi: 10.1200/JCO.2017.77.0388. Epub 2018 Mar 27.

  PMID: 29584545 BACKGROUND

• Zarrabi K, Fang C, Wu S. New treatment options for metastatic renal cell carcinoma with prior anti-angiogenesis therapy. J Hematol Oncol. 2017 Feb 2;10(1):38. doi: 10.1186/s13045-016-0374-y.

  PMID: 28153029 BACKGROUND

• Chong WQ, Low JL, Tay JK, Le TBU, Goh GS, Sooi K, Teo HL, Cheo SW, Wong RT, Samol J, Lim MY, Li H, Shirgaonkar N, Chia S, Wang L, Gopinathan A, Eu DK, Tsang RK, Loh KS, Toh HC, Syn N, Kong LR, Dasgupta R, Tai BC, Lim YC, Goh BC. Pembrolizumab with or without bevacizumab in platinum-resistant recurrent or metastatic nasopharyngeal carcinoma: a randomised, open-label, phase 2 trial. Lancet Oncol. 2025 Feb;26(2):175-186. doi: 10.1016/S1470-2045(24)00677-6. Epub 2025 Jan 15.

  PMID: 39826567 DERIVED

MeSH Terms

Conditions

Nasopharyngeal Neoplasms; Epstein-Barr Virus Infections

Interventions

pembrolizumab; Bevacizumab

Condition Hierarchy (Ancestors)

Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Neoplasms by Site; Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Boon Cher Goh

  National University Hospital, Singapore

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Eligible patients will be randomized 1:1 into either Treatment Arm A or Arm B. Treatment will continue until tumor progression, intolerance to treatment, or up to 2 years (32 doses of pembrolizumab/bevacizumab). For patients who have progressed on pembrolizumab alone, cross over to Arm B is allowed, with repeat biopsy of the lesions before and 1 week after starting bevacizumab. Patients who discontinue from the trial will not be replaced.

Study Record Dates

• First Submitted: January 20, 2019
• First Posted: January 23, 2019
• Study Start: May 1, 2019
• Primary Completion: July 31, 2024
• Study Completion: June 1, 2025
• Last Updated: November 22, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: This will be available beginning 3 months after article publication with no end date.
• Access Criteria: Researchers whose proposed use of the data has been approved by an independent ethics review committee can access the data to achieve the aims in the proposal. Proposals should be directed to the corresponding author to provide data access following signing a data access agreement. The data will be made available by a link sent from the corresponding author to the requester.

Locations

SG (1)