Clinical Trial Results:
Phase IIa/IIb Clinical Trial of NC-6004 in Combination with Pembrolizumab in Subjects with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Who Have Failed Platinum or a Platinum-containing Regimen
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Summary
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EudraCT number |
2018-003959-37 |
Trial protocol |
HU PL CZ HR |
Global end of trial date |
30 Jun 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Mar 2024
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First version publication date |
15 Mar 2024
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Other versions |
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Summary report(s) |
CSR Synopsis |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NC-6004-009
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03771820 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Nano Carrier Co, Ltd
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Sponsor organisation address |
Ohnoya-Kyobashi Bldg 1-4-10 Kyobashi, Chuo-ku, Tokyo, Japan, 104-0031
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Public contact |
Study Director, NanoCarrier Co, Ltd., +81 3-3241-0551, osada@nanocarrier.co.jp
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Scientific contact |
Study Director, NanoCarrier Co, Ltd., +81 3-3241-0551, osada@nanocarrier.co.jp
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
05 Jan 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Jun 2022
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Part 1(Phase IIa):
To assess dose-limiting toxicities (DLTs), and to determine the optimal dose in order to establish the recommended Phase IIb (RPIIb) dose for the combination of NC-6004 plus pembrolizumab.
Part 2 (Phase IIb):
To compare progression-free survival (PFS) between NC-6004 plus pembrolizumab and pembrolizumab alone.
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Protection of trial subjects |
The study protocol, consent form, participant recruitment process and other relevant study documents were submitted to involved Ethic Committee (ECs)/Independent Ethic Committees (IECs) and approved prior to study initiation. This study was conducted in accordance with principles of the Declaration of Helsinki, with the current
Good Clinical Practice guidelines and with other applicable local regulations. The investigators and their study staff conducted the study in compliance with the study protocol and further protocol amendments.
Interested participants were given an opportunity to discuss the activities and procedures involved in study participation with the principal investigator and their site staff. An EC-approved informed consent form which was given to the potential subject and an opportunity afforded to read the consent form and ask questions. Those individuals interested in participation were requested to sign the informed consent form prior to the performance of any study-related procedures.
The rights, safety, and wellbeing of the study subjects were the most important considerations and prevailed over the interests of science and society.
Identifying any untoward medical occurrence and timely and complete reporting of all AEs was aimed at the most efficient protection of the safety of study subjects.
Patient's personal, medical and sensitive data were protected in line with general (GDPR) and applicable local data protection regulations.
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Background therapy |
Platinum compounds are well established agents in the treatment of cancer (Kelland and Sharp 1999). The leading platinum compounds in cancer chemotherapy are cisplatin, carboplatin, and oxaliplatin. They share a number of common structural chemical characteristics; however, they exhibit marked interanalogue differences in pharmacokinetics, side effect profiles, and optimal therapeutic indication. Cisplatin has been widely used for the treatment of cancer, including lung cancer (both small cell lung cancer and NSCLC), head and neck cancer, germ-cell tumors (testicular, ovarian, and extragonadal germ cell tumor), ovarian cancer, testicular tumor, bladder cancer, renal pelvis/ureter tumor, prostate cancer, esophagus cancer, cervical cancer, neuroblastoma, stomach cancer, osteosarcoma, and pleura malignant mesothelioma in monotherapy, and malignant bone tumors, endometrial cancer (adjuvant chemotherapy and chemotherapy for metastasis/recurrence), recurrent/refractory malignant lymphoma, and pediatric malignant solid tumors (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, and other primary malignant liver tumors, medulloblastoma) in combination therapy. The mechanism of action of cisplatin is the inhibition of DNA synthesis induced by the platinum-DNA adduct formed by cross-linking between cisplatin and specific base sequences. This cross-linking inhibits DNA replication and transcription and activates signal transduction pathways leading to apoptosis and cell death (Pinto and Lippard 1985). | ||
Evidence for comparator |
Immune checkpoint inhibitors, such as pembrolizumab, are approved for treatment in people with recurrent or metastatic head and neck cancer who are currently on or have received platinum-containing chemotherapy. In oncology development, there are many ongoing trials that show better efficacy from combination agents have already been developed, showing an acceptable tolerance with a significant clinical activity. | ||
Actual start date of recruitment |
14 Jun 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 15
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Country: Number of subjects enrolled |
Croatia: 7
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Country: Number of subjects enrolled |
Czechia: 7
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Country: Number of subjects enrolled |
Hungary: 9
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Country: Number of subjects enrolled |
Taiwan: 13
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Country: Number of subjects enrolled |
Russian Federation: 20
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Country: Number of subjects enrolled |
Serbia: 38
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Country: Number of subjects enrolled |
Ukraine: 43
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Worldwide total number of subjects |
152
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EEA total number of subjects |
38
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
152
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 220 subjects were screened in this study, 16 subjects in Phase IIa and 204 subjects in Phase IIb. Of 204 subjects screened for Phase IIb, 136 subjects were randomized and 68 subjects were screen failure. Of the 136 subjects, 31 subjects were excluded from the Full Analysis Set (FAS) and 105 subjects received treatment. | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Days -28 -1: ICF, demographic data, medical/surgical/cancer history, disease status, tumor sampling. Days -14 -1: height, weight; body surface area, CT/MRI, ECOG Performance Status, audiometry, ophthalmologist, cardiac risk factor, medications, vaccinations, AEs. Days -7 -1: eligibility criteria, pregnancy test, FSH, physical examination, etc. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Treatment period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
Blinding implementation details |
Not applicable
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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NC-6004 and Pembrolizumab | ||||||||||||||||||||||||||||||
Arm description |
In the first arm patients were treated with NC-6004 and Pembrolizumab. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
NC-6004
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Investigational medicinal product code |
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Other name |
Cisplatin-PEG-pGlu
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects were administered with NC-6004 first followed by pembrolizumab in both parts of the study. The Part 1 phase IIa portion, starting dose was 90 mg/m2 , with subsequent dose escalations to 105 mg/m2 , 120 mg/m2 , and 135 mg/m2 . In phase IIb portion, the dose was to be determined RPII dose in phase IIa portion.
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Investigational medicinal product name |
Pembrolizumab
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Investigational medicinal product code |
L01XC18
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Other name |
KEYTRUDA
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
The recommended dose of pembrolizumab was 200 mg administered as an IV infusion over 30 minutes every 3 weeks.
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Arm title
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Pembrolizumab | ||||||||||||||||||||||||||||||
Arm description |
In the second arm patients were treated with Pembrolizumab alone. | ||||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Pembrolizumab
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Investigational medicinal product code |
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Other name |
KEYTRUDA
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
The recommended dose of pembrolizumab was 200 mg administered as an IV infusion over 30 minutes every 3 weeks.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: A total of 220 subjects were screened at baseline period this study. Only 152 subjects were enrolled. |
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Baseline characteristics reporting groups
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Reporting group title |
NC-6004 and Pembrolizumab
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Reporting group description |
In the first arm patients were treated with NC-6004 and Pembrolizumab. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Pembrolizumab
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Reporting group description |
In the second arm patients were treated with Pembrolizumab alone. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety Population (SP)
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Safety Population (SP) included all participants who received at least one dose of study drug NC-6004 and/or one dose of pembrolizumab. This population was used for analyses of safety data. It was used for summary of baseline data and analyses of progression free survival (PFS).
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Subject analysis set title |
Response Evaluable Population (REP)
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Response Evaluable Population (REP) included all participants who received at least one dose of study drug NC-6004 and/or one dose of pembrolizumab, had baseline measurable disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1]), and had at least one post-baseline radiographic tumor assessment or discontinued study treatment due to clinical progression determined by the site investigator or death if no post-baseline tumor assessment. This population was used for summary of tumor assessment data and analyses of response rates.
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End points reporting groups
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Reporting group title |
NC-6004 and Pembrolizumab
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Reporting group description |
In the first arm patients were treated with NC-6004 and Pembrolizumab. | ||
Reporting group title |
Pembrolizumab
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Reporting group description |
In the second arm patients were treated with Pembrolizumab alone. | ||
Subject analysis set title |
Safety Population (SP)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The Safety Population (SP) included all participants who received at least one dose of study drug NC-6004 and/or one dose of pembrolizumab. This population was used for analyses of safety data. It was used for summary of baseline data and analyses of progression free survival (PFS).
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Subject analysis set title |
Response Evaluable Population (REP)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The Response Evaluable Population (REP) included all participants who received at least one dose of study drug NC-6004 and/or one dose of pembrolizumab, had baseline measurable disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1]), and had at least one post-baseline radiographic tumor assessment or discontinued study treatment due to clinical progression determined by the site investigator or death if no post-baseline tumor assessment. This population was used for summary of tumor assessment data and analyses of response rates.
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End point title |
To establish the Recommended Phase IIb (RPIIb) dose [1] | |||||||||
End point description |
To assess (DLTs), and to determine the optimal dose in order to establish the RPIIb dose for the combination of NC 6004 plus pembrolizumab an Independent Data Monitoring Committee was involved in this part. No statistical analyzes planned.
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End point type |
Primary
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End point timeframe |
From the first day of treatment to the end of the follow-up period of the study.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: this study was early terminated. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
To determine the Progression-Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) [2] | |||||||||
End point description |
To determine the Progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in eligible subjects after treatment with NC-6004 plus pembrolizumab and pembrolizumab alone.
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End point type |
Primary
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End point timeframe |
From the first day of treatment to the end of the follow-up period of the study.
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: this study was early terminated. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Incidences and severity of SAEs, TEAEs, and discontinuation because of TEAEs | |||||||||
End point description |
Incidences and severity of serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), and discontinuation because of TEAEs
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End point type |
Secondary
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End point timeframe |
From the first day of treatment to the end of the follow-up period of the study.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Incidence and severity of laboratory abnormalities | |||||||||
End point description |
Incidence and severity of laboratory abnormalities (hematology and biochemistry) according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.
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End point type |
Secondary
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End point timeframe |
From the first day of treatment to the end of the follow-up period of the study.
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| Notes [3] - Not done. [4] - Not done. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change from baseline in vital sign measurements | |||||||||
End point description |
Change from baseline in vital sign measurements (blood pressure, heart rate, respiratory rate, and temperature)
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End point type |
Secondary
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End point timeframe |
From the first day of treatment to the end of the follow-up period of the study.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change from baseline in electrocardiogram (ECG) findings | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From the first day of treatment to the end of the follow-up period of the study.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Overall survival subjects | ||||||||||||||||
End point description |
OS is defined as the time from randomization/inclusion to death due to any cause or last contact.
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End point type |
Secondary
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End point timeframe |
From the first day of treatment to the end of the follow-up period of the study.
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| Notes [5] - Not done. [6] - Not done. [7] - Not done. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Overall response rate (ORR) | |||||||||
End point description |
ORR is defined as the proportion of subjects who have a complete response (CR) defined as a disappearance of all target lesions with pathological lymph nodes having a reduction in short axis to <10 mm, or partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions, using the baseline sum diameters as a reference.
ORR was assessed by performing study imaging at 6 weeks (42 days ±7 days) and again at 12 weeks (84 days ±7 days) from the date of first study dose. Subsequent tumor imaging was performed every 9 weeks (63 days ±7 days) after the last imaging or more frequently if clinically indicated. After 48 weeks, subjects who remain on treatment had imaging performed every 12 weeks (84 days ±7 days) after the last imaging.
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End point type |
Secondary
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End point timeframe |
From the first day of treatment to the end of the follow-up period of the study.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Complete response (CR)/ Partial response (PR) | |||||||||
End point description |
CR defined as disappearance of all target and all non-target lesions. All pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm.
PR defined as at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
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End point type |
Secondary
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End point timeframe |
From the first day of treatment to the end of the follow-up period of the study.
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| No statistical analyses for this end point | ||||||||||
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End point title |
Stable disease (SD) | |||||||||
End point description |
SD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).
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End point type |
Secondary
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End point timeframe |
From the first day of treatment to the end of the follow-up period of the study.
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| Notes [8] - Not done. [9] - Not done. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Duration of response (DOR) | |||||||||
End point description |
DOR defined as subjects who demonstrated confirmed CR or PR. DOR is defined as the time from first documented evidence of CR or PR until disease progression or death.
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End point type |
Secondary
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End point timeframe |
From the first day of treatment to the end of the follow-up period of the study.
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| Notes [10] - Not done. [11] - Not done. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Time to response (TTR) | ||||||||||||
End point description |
TTR defined as subject’s first documented response from the date of randomization/inclusion.
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End point type |
Secondary
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End point timeframe |
From the first day of treatment to the end of the follow-up period of the study.
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| Notes [12] - Not done. [13] - Not done. |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
From screening to the end of the study.
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Assessment type |
Systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||
Dictionary version |
24
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| Frequency threshold for reporting non-serious adverse events: 3% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: The analysis included only TEAEs, i.e., AEs that started or worsened after the start of IMP. All TEAEs, related TEAEs (i.e., TEAEs probably or possibly related to the IMP), and serious TEAEs were summarized and tabulated according to MedDRA primary system organ class and preferred term. |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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21 Feb 2019 |
Protocol updated with regards to the exclusion criteria in connection with comments received from the Hungarian regulatory authority (OGYEI). |
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26 Nov 2019 |
Protocol submitted only in Taiwan and then updated in line with comments received from Taiwanian FDA, which resulted in creation of Protocol version 4.0 submitted globally. |
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04 May 2020 |
Main changes:
• Clarification of study objectives and endpoints
• Clarification of inclusion criteria
• Clarification and addition of exclusion criteria upon TFDA request
• Change to adaptive randomization
• Change in reasons for patient withdrawal from the study due to toxicity upon TFDA request
• Change in dose-limiting toxicity criteria upon TFDA request
• Clarification of efficacy assessments
• Change in prophylactic medication as per FDA recommendation and the Sponsor’s medical monitors recommendation |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None | |||
