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ONO-7912 Phase I Study A multicenter, open-label, uncontrolled study in pancreatic cancer (ONO-7912-01)

ONO-7912 Phase I Study (ONO-7912-01)

8

Japanese patients with pancreatic cancer who were refractory to or intolerant of chemotherapy including gemcitabine. Of the 8 subjects in the Safety Analysis Set (SAF), 7 subjects (87.5%) were female. The median age (range) was 65.5 years (48-72), with 4 subjects (50.0%) in each of the under 65 years and 65 years or older. The Eastern Cooperative Oncology Group (ECOG) Performance Status was 0 in 6 subjects (75.0%) and 1 in 2 subjects (25.0%). Seven subjects (87.5%) were primary pancreatic cancer, and the median (range) number of days from the date of the initial diagnosis to the date of enrollment was 225.0 days (61-740). In addition, for the 1 subject (12.5%) of recurrent pancreatic cancer, the number of days from the date of recurrence to the date of enrollment was 301 days. The most common primary site was the pancreatic head in 4 subjects (50.0%), followed by the pancreatic body in 2 subjects (25.0%) and the pancreatic tail in 1 subject (12.5%). All subjects were classified as Stage IV; the number of metastatic sites was 1 in 5 subjects (62.5%) and 2 in 3 subjects (37.5%). The sites of metastasis were the lungs in 4 subjects (50.0%), the liver in 3 subjects (37.5%), lymph nodes in 2 subjects (25.0%), and the peritoneal cavity and other sites in 1 subject each (12.5%). One subject (12.5%) had a history of surgery for pancreatic cancer, and all subjects had a history of drug therapy for pancreatic cancer; however, none had a history of radiation therapy for pancreatic cancer. Furthermore, no procedures to relieve jaundice had been performed.

This clinical trial was a multicenter, open-label, uncontrolled, dose-escalation Phase 1 study conducted at 2 sites to evaluate the safety and tolerability of ONO-7912 when administered in combination with mFFX therapy. Eight patients continued to receive ONO-7912 until they met the discontinuation criteria for ONO-7912. If mFFX therapy was postponed, administration of ONO-7912 was also postponed. Discontinuation of each agent of the mFFX therapy was carried out at the discretion of the principal investigator or a sub-investigator, in accordance with the clinical trial protocol.

Among the 6 subjects in the dose-limiting toxicity (DLT) evaluation cohort who received ONO-7912 250 mg per square meters, a DLT (febrile neutropenia) was observed in 1 subject, and 250 mg per square meters was considered to be tolerable. In the 8 subjects in the SAF group, adverse events and drug-related adverse events were observed in all subjects. Adverse events observed in 2 or more subjects included neutrophil count decreased in 6 subjects (75.0%), nausea in 4 subjects (50.0%), diarrhoea in 3 subjects (37.5%), and constipation, peripheral sensory neuropathy, dysarthria, decreased appetite, hiccups, and febrile neutropenia in 2 subjects each (25.0%). In addition, drug-related adverse events observed in 2 or more subjects included neutrophil count decreased in 6 subjects (75.0%), nausea in 4 subjects (50.0%), diarrhoea in 3 subjects (37.5%), and peripheral sensory neuropathy, dysarthria, decreased appetite, and febrile neutropenia in 2 subjects each (25.0%). Grade 3 or higher adverse events were observed in 7 subjects, including neutrophil count decreased in 3 subjects (37.5%), febrile neutropenia in 2 subjects (25.0%), and diarrhoea, ascites, gamma-glutamyltransferase increased, peripheral sensory neuropathy, and biliary obstruction in 1 subject each (12.5%). Grade 3 or higher drug-related adverse events were observed in 6 subjects, including neutrophil count decreased in 3 subjects (37.5%), febrile neutropenia in 2 subjects (25.0%), and diarrhoea, gamma-glutamyltransferase increased, and peripheral sensory neuropathy in 1 subject each (12.5%). No subjects died within 28 days after the final administration of ONO-7912 or mFFX therapy, or by the date of initiation of subsequent treatment, whichever came first. Subsequently, 3 subjects died during the study period and in all subjects, the cause of death was the underlying disease. Serious adverse events were observed in 2 subjects (25.0%), including diarrhoea and febrile neutropenia in 1 subject each (12.5%), and all were considered to be drug-related. The outcomes were resolved and recovered, respectively. Adverse events leading to discontinuation of the investigational drug (ONO-7912 or mFFX therapy) were observed in 5 subjects (62.5%), and all were considered to be drug-related. All events that occurred were neutrophil count decreased, and the outcome in each event was recovered. Adverse events leading to a dose reduction of the investigational drug (mFFX therapy) were observed in 3 subjects (37.5%), including peripheral sensory neuropathy, diarrhoea, neutrophil count decreased, and febrile neutropenia in 1 subject each (12.5%), and all were considered to be drug-related. With the exception of 1 subject of peripheral neuropathy that did not resolve, all subjects resolved. Adverse events leading to discontinuation of the investigational drug (ONO-7912 or mFFX therapy) were observed in 2 subjects (25.0%), including peripheral sensory neuropathy and febrile neutropenia in 1 subject each (12.5%), and all were considered to be drug-related. The outcome was not recovered for peripheral sensory neuropathy and recovered for febrile neutropenia. Most abnormalities in laboratory test values observed after the start of investigational drug administration were Grade 1 or 2. No subjects had a QTcF exceeding 500 ms after the start of investigational drug administration, nor were there any subjects who exhibited a QTcF prolongation of more than 60 ms from baseline.

The primary endpoint of this clinical trial was safety, and no primary efficacy endpoint was specified.

Efficacy results: Based on results of radiological assessments evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines Version 1.1, the objective response rate (ORR) [95% confidence interval (CI)] as determined by physicians at the treating institutions was 12.5% [0.3, 52.7] (1 of 8 subjects), and the disease control rate (DCR) [95%CI] was 37.5% [8.5, 75.5] (3 of 8 subjects). The median overall survival (OS) [95%CI], calculated using the Kaplan-Meier method, had not been reached [2.63, not available (N.A.)]; the overall survival rate [95%CI] was 87.5% [38.7, 98.1] at both 3 and 6 months, 60.0% [19.5, 85.2] at 12 months, and had not been reached [N.A., N.A.] at both 18 and 24 months. The median progression free survival (PFS) [95%CI], calculated using the Kaplan-Meier method, was 8.31 months [0.46, N.A.], and the progression-free survival rate [95%CI] was 54.7% [13.7, 83.2] at both 3 and 6 months, 36.5% [5.3, 70.6] at 12 months, and had not been reached [N.A., N.A.] at both 18 and 24 months. The duration of response (DOR) at the time of discontinuation for the 1 subject who achived a response according to RECIST Guidelines Version 1.1 was 3.5 months, and the time to response (TTR) was 5.1 months. In the best overall response (BOR) assessment using RECIST Guidelines Version 1.1, no subjects achieved complete response or complete remission (CR); there was 1 subject (12.5%) with partial response (PR), 2 subjects (25.0%) with stable disease (SD), 3 subjects (37.5%) with progressive disease (PD), and 2 subjects (25.0%) with not evaluable (NE). Tumor regression was observed in 7 of the 8 subjects. Pharmacokinetic results: Plasma concentrations of ONO-7912 decreased rapidly following administration of ONO-7912 and were almost undetectable 24 hours after the start of administration. Furthermore, plasma concentrations of CPI-2850 (active metabolite of ONO-7912) were also almost undetectable 48 hours after the start of ONO-7912 administration. No accumulation was observed with either ONO-7912 or CPI-2850 following repeated administration.

Based on the results of this clinical trial, the combination regimen of ONO-7912 (250 mg per square meters) and mFFX therapy was considered to be well tolerated in Japanese patients with pancreatic cancer who were refractory to or intolerant of chemotherapy including gemcitabine.

No

ONO PHARMACEUTICAL CO., LTD.

1-8-2 Kyutaromachi, Chuo-ku Osaka-shi, Osaka-fu Japan

clinical_trial@ono-pharma.com

ONO PHARMACEUTICAL CO., LTD.

1-8-2 Kyutaromachi, Chuo-ku Osaka-shi, Osaka-fu Japan

+81-120278120

clinical_trial@ono-pharma.com

completed

Oct. 01, 2020

Interventional

A multicenter, open-label, uncontrolled study

treatment purpose

1

1. Patients diagnosed with invasive pancreatic ductal carcinoma determined as adenocarcinoma histologically or cytologically
2. Patients who received one regimen of chemotherapy including gemcitabine for pancreatic cancer.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
4. Have a life expectancy of at least 90 days

1. Patients in whom oxaliplatin, irinotecan, fluorouracil, or levofolinate calcium is contraindicated
2. Patients with clinically relevant diarrhea (including watery stools)
3. Patients with grade >=2 peripheral motor neuropathy or peripheral sensory neuropathy
4. Patients who have received ONO-7912

Both

Patients with pancreatic cancer refractory or intolerance to chemotherapy including gemcitabine

investigational material(s)
Generic name etc : devimistat (ONO-7912)
INN of investigational material : devimistat
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Intravenous administration

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

safety
Tolerability, safety

efficacy
exploratory
pharmacokinetics
Overall response rate, disease control rate, overall survival

Sept. 14, 2020