Clinical trial NCT05283226: Study to Evaluate the Safety and Efficacy of Oral NRC-2694-A in Combination With Paclitaxel in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma, Who Progressed on or After Immune Checkpoint Inhibitor Therapy
Official title: A Phase 2 Multicenter, Open-Label, Single-Arm Study to Evaluate the Safety and Efficacy of Oral NRC-2694-A in Combination With Paclitaxel in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma, Who Progressed on or After Immune Checkpoint Inhibitor Therapy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Carcinoma
Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma
Keywords: Carcinoma
Recurrent and/or Metastatic Cancer
Lead sponsor: NATCO Pharma Ltd.
Sponsor class: INDUSTRY
First posted: 2022-03-16
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a Phase 2, open-label, multicenter, single-arm study of NRC-2694-A in combination with paclitaxel in patients with R/M HNSCC with progression on or after ICI therapy.

A total of approximately 46 male and female patients will be enrolled. This sample size is based on Simon's 2-stage design with historical control ORR of 30% and a target ORR of 50%.

Detailed description: Patients with recurrent and/or metastatic unresectable Head and Neck Cancer have a poor prognosis and limited treatment options. Pembrolizumab and Nivolumab, both ICIs (Immune Checkpoint Inhibitors), are approved therapies for this condition. However, no approved treatment options exist for patients who progress on ICI therapies. Hence, there is an unmet medical need post-failure of ICI therapy. NRC-2694-A is an orally administered small-molecule tyrosine kinase inhibitor. It was discovered and developed by NATCO Pharma Ltd. NRC-2694-A demonstrated response in HNSCC patients in a Phase-I study as a monotherapy. This was further substantiated in a Phase-II study in combination with cisplatin/carboplatin and paclitaxel.

Eligibility criteria: Inclusion Criteria:

* Is willing and capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements.
* Is male or female aged 18 years or older at the time of consent.
* Has histologically confirmed unresectable R/M HNSCC (oral cavity, oropharynx, hypopharynx, and larynx).
* Has documented progressive disease assessed by the principal investigator according to RECIST v1.1.
* Has a measurable lesion per RECIST v1.1.
* Has ECOG performance status score of ≤2.
* Must have progressed during or after receiving ICI therapy, such as pembrolizumab or nivolumab. Patients with prior immune-mediated reactions due to ICI therapies (eg, pembrolizumab or nivolumab) and who had recovered prior to study entry will also be eligible.
* Female patients of childbearing potential should have a negative urine test before enrollment. If the urine pregnancy test is positive or gives equivocal results, a serum pregnancy will be required for confirmation.
* Patients of reproductive age must use acceptable methods of contraception throughout the study period and for 30 days following the last dose of investigational product (see protocol for further guidance).
* During screening and at subsequent visits, the investigator should ensure adequate bone marrow reserve (neutrophil count ≥1500/mm3, platelet count ≥100,000/mm3, and hemoglobin level 8.0 g/dL), renal function (creatinine clearance ≥30 mL/min calculated by Cockcroft-Gault formula), liver function (total bilirubin level ≤1.5 × ULN \[except patients with documented Gilbert's syndrome\] and serum transaminase levels ≤2.5 × ULN or ≤5 × ULN for liver metastasis and/or obstructive jaundice).
* Must have completed a duration of at least two weeks after stopping ICI therapy/investigational therapy/salvage therapy and must have recovered to grade ≤1 from all toxicities due to such therapies.

Exclusion Criteria:

* Has cardiac, hepatic, endocrine, pulmonary, or autoimmune disease, interstitial lung disease, renal or psychiatric disorders, not controlled with therapy corresponding to the illness or a condition that contraindicates the use of a taxane or an EGFR inhibitor.
* Has Cirrhosis of liver at a level of Child-Pugh B (or worse).
* Has uncontrolled brain metastases. Patients are allowed if brain metastasis has been previously treated with surgery, whole brain irradiation, and/or stereotactic radiosurgery and are considered controlled (controlled by the dose ≤10 mg/day of prednisone or equivalent) at the time of the first dose of investigational product. Radiological evaluation of brain metastasis will be performed only if the patient has symptoms. For asymptomatic patients, brain imaging during screening is not required.
* Has baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval \>480 milliseconds \[CTCAE Grade 1\] using Fredericia's QT correction formula).
* Has a history of additional risk factors for Torsade de pointes (eg, heart failure, hypokalemia, family history of long QT syndrome).
* Has had prior cetuximab therapy for recurrent or metastatic disease. Note that cetuximab used concomitantly with radiotherapy or as an induction therapy is acceptable
* Has received any other EGFR-targeted therapies for recurrent or metastatic disease.
* Currently participating in any clinical trial or receiving investigational therapy on expanded access or compassionate basis.
* Has nasopharyngeal carcinomas or salivary gland cancers.
* Female patient who tested positive for pregnancy.
* Female patient who is breastfeeding or planning to become pregnant, or male patient planning to father a child within the duration of the study.
* Has tested positive for HIV, HBsAg, HCV antibody, or HCV RNA at screening. However, patients who test positive for HCV antibody, but negative for HCV RNA, will be allowed. In addition, patients with controlled HIV, chronic HBV on suppressive antiviral therapy, or a history of HCV infection status post-curative antiviral treatment with an HCV viral load below limit of quantification are permitted to participate (DHHS 2020).
* Has active infection requiring intravenous anti-infective therapy within 7 days prior to Day 1 Cycle 1 or is febrile due to infection.
* Has had major surgery within 4 weeks prior to screening.
* Administered a live attenuated vaccine within 4 weeks prior to Day 1 Cycle 1 or anticipation that such a live attenuated vaccine will be required during the study.
* Has known or suspected hypersensitivity to any components of the formulation used for this investigational product.
* Has concurrent disease or any clinically significant abnormality following the investigator's review of the screening physical examination findings, 12-lead ECG results, and clinical laboratory tests, which in the judgment of the investigator would interfere with the patient's participation in this study or evaluation of study results.
* Unable to come for study visits per schedule.
* Has current drug or alcohol abuse.
* Has received prior treatment with paclitaxel or docetaxel or any other drugs with taxane like mode of action for recurrent or metastatic or recurrent HNSCC. However, prior paclitaxel or docetaxel or any other drugs with taxane like mode of action as a component of a curatively-intended multimodality treatment for locally advanced HNSCC is permitted.

Primary outcomes:
measure: To determine if NRC-2694-A administered orally in combination with paclitaxel demonstrates objective response in patients with R/M HNSCC, who have had radiological progression on or after treatment with ICI therapies like pembrolizumab or nivolumab
timeFrame: Baseline through approximately up to 24 weeks
Secondary outcomes:
measure: Progression-free survival
timeFrame: Baseline through approximately up to 24 weeks
measure: Overall survival
timeFrame: Baseline through approximately up to 24 weeks
measure: Duration of response
timeFrame: Baseline through approximately up to 24 weeks
measure: Clinical benefit response
timeFrame: Baseline through approximately up to 26 weeks
measure: Number of adverse events
timeFrame: Baseline through approximately up to 24 weeks
measure: Number of participants with abnormal physical examination findings
timeFrame: Baseline through approximately up to 24 weeks
measure: Number of participants with abnormal vital signs
timeFrame: Baseline through approximately up to 24 weeks
measure: Assessing safety through ECOG (Eastern Cooperative Oncology Group)
timeFrame: Baseline through approximately up to 24 weeks
measure: Number of participants with abnormal clinical laboratory tests results
timeFrame: Baseline through approximately up to 24 weeks
measure: Number of participants with abnormal ECGs (Electrocardiograms)
timeFrame: Baseline through approximately up to 24 weeks
measure: Plasma PK parameters of NRC-2694-A measured via Cmax (Maximum plasma concentration)
timeFrame: Baseline through approximately up to 24 weeks
measure: Plasma PK parameters of NRC-2694-A measured via Tmax (time to reach the maximum plasma concentration)
timeFrame: Baseline through approximately up to 24 weeks
measure: Plasma PK parameters of NRC-2694-A measured via Ctrough (observed trough plasma concentration at the dosing interval tau)
timeFrame: Baseline through approximately up to 24 weeks
measure: Plasma PK parameters of NRC-2694-A measured via AUC0-t (area under the concentration-time curve from time zero to the time of last measurable concentration)
timeFrame: Baseline through approximately up to 24 weeks
measure: Plasma PK parameters of NRC-2694-A measured via AUC0-τ (area under the concentration-time curve from time zero to the dosing interval tau)
timeFrame: Baseline through approximately up to 24 weeks
measure: Plasma PK parameters of NRC-2694-A measured via CL/F (apparent clearance)
timeFrame: Baseline through approximately up to 24 weeks
measure: Plasma PK parameters of NRC-2694-A measured via Vz/F (apparent volume of distribution)
timeFrame: Baseline through approximately up to 24 weeks
measure: Plasma PK parameters of NRC-2694-A measured via Rac Cmax (accumulation ratio based on maximum plasma concentration)
timeFrame: Baseline through approximately up to 24 weeks
measure: Plasma PK parameters of NRC-2694-A measured via Rac AUC (accumulation ratio based on area under the concentration-time curve)
timeFrame: Baseline through approximately up to 24 weeks
Other outcomes:
measure: To determine the association between NRC-2694-A activity and biomarkers in blood samples using Epidermal growth factor receptor status in EGFR (epidermal growth factor receptor) gene
timeFrame: Baseline through approximately up to 24 weeks
measure: To determine the association between NRC-2694-A activity and biomarkers in blood samples using downstream signaling in EGFR gene
timeFrame: Baseline through approximately up to 24 weeks
measure: To determine the association between NRC-2694-A activity and biomarkers in blood samples using mutations in EGFR gene
timeFrame: Baseline through approximately up to 24 weeks
Locations:
city: Fullerton
country: United States
facility: Providence Medical Foundation -Fullerton
state: California
city: Los Angeles
country: United States
facility: Los Angeles Hematology Oncology Medical Group
state: California
city: Boca Raton
country: United States
facility: Lynn Cancer Center
state: Florida
city: Miami
country: United States
facility: Miami Cancer Center
state: Florida
city: Louisville
country: United States
facility: Norton Cancer Institute - Downtown
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland Greenebaum Cancer Center
state: Maryland
city: Saint Louis
country: United States
facility: Washington University - Siteman Cancer Center
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Easton
country: United States
facility: Salib Oncology
state: Pennsylvania
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center
state: Wisconsin
city: Mumbai
country: India
facility: Daycare Angels under AOH
state: Maharashtra
city: Pune
country: India
facility: Grant Medical Foundation Ruby Hall Clinic
state: Maharashtra
Study officials:
References: