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A Phase Ib study to evaluate the safety and efficacy of combination therapy with Nivolumab and Photoimmunotherapy (PIT) using ASP-1929 for the patients with unresectable advanced/recurrent gastric cancer or esophageal cancer

GE-PIT Study

21

ITT (Intention to treat) population in the Dose escalation part and in the Expansion part was 9 patients and 12 patients, respectively. Age in the Dose escalation part and in the Expansion part was 69.7 +- 7.3 years (mean +- SD) and 70.3 +- 11.3 years, respectively; BMI was 19.60 +- 5.41 kg/m2 and 21.49 +- 2.77 kg/m2, respectively. No patients with double cancer or photosensitivity had been observed. EGFR expression in the Dose escalation part and in the Expansion part was 1+ in 1 patient (11.1%) and 1 patient (8.3%), respectively, 2+ in 5 patients (55.6%) and 7 patients (58.3%), respectively, and 3+ in 3 patients (33.3%) and 4 patients (33.3%), respectively; PD-L1 positive in 4 patients (44.4%) and 7 patients (58.3%), respectively, and PD-L1 negative in 5 patients (55.6%) and 5 patients (41.7%), respectively. Although this study planned to be conducted in patients with unresectable advanced/recurrent gastric cancer or esophageal cancer, all 21 patients had gastric cancer and no patients with esophageal cancer were enrolled.

<Dose escalation part> Signed informed consent: 9 patients Registered: 9 patients <Expansion part> Signed informed consent: 13 patients Registered: 12 patients

Adverse events leading to death occurred in 3 patients in the Dose escalation part: pneumonia pneumococcal, malignant neoplasm progression, and pleural effusion (1 patient each). None of them were assessed as related to the study treatment. Other serious adverse events occurred in 3 patients in the Expansion part: oesophagitis, septic shock, and pneumonitis (1 patient each). All of them were serious due to [hospitalization or prolonged hospitalization]. Additionally, septic shock was assessed as [life-threatening]. Septic shock and pneumonitis were assessed as adverse drug reactions to nivolumab, while oesophagitis was assessed as an adverse drug reaction to ASP-1929-PIT. Adverse events were reported in 10 patients (83.3%) in the Expansion part and those that occurred in >=2 patients were pyrexia and rash (33.3%; 4 events in 4 patients for each event), stomatitis (16.7%; 3 events in 2 patients), and ascites, oesophagitis, application site pain, hepatic function abnormal, decreased appetite, and pruritus (16.7%; 2 events in 2 patients for each event). Adverse drug reactions were reported in 10 patients (83.3%) and those that occurred in >=2 patients were rash (25.0%; 3 events in 3 patients), stomatitis (16.7%, 3 events in 2 patients), and oesophagitis, application site pain, pyrexia, and hepatic function abnormal (16.7%; 2 events in 2 patients for each event). That of Grade 4 was septic shock (8.3%; 1 patient), which occurred in the Expansion part; the event of septic shock was assessed as an adverse drug reaction to nivolumab. Treatment discontinuation was reported in 4 patients (33.3%) in the Expansion part : stomatitis, hepatic function abnormal, herpes zoster, septic shock, decreased apetitie, pneumonitis and rash (1 patient each). All of them, other than herpes zoster, were assessed as adverse drug reactions to nivolumab. In the Dose escalation part, pneumonia which occured in 1 patient was assessed as an adverse drug reaction to nivolumab. Nivolumab was discontinued in all 5 patients and ASP-1929 was additionally discontinued in 1 patient with pneumonitis. In the Dose escalation part, device malfunctions of [unable to remove stylet], [thermal damage to balloons and diffusers], and [cannot insert light diffuser] occurred in 1 patient and [irradiation did not start] occurred in another patient. There were no adverse events or health hazards to individuals other than patients due to laser equipment malfunctions.

<For Dose escalation part only> Proportion of incidence of DLTs (Dose-limiting toxicity): No DLT was observed (DLT incidence was 0%) for the 9 patients of DLT Evaluation Population during the DLT evaluation period (Days 8 - 14, in the Dose escalation part).

< For both Dose escalation part and Expansion part > Efficacy results: In the Expansion part of 12 patients, the number of patients who achieved either CR (Complete response) or PR (Partial response) in terms of the investigator-assessed best overall response per RECIST guideline ver. 1.1 was 1 patient (who achieved PR), and the ORR(Objective response rate) was 8.3% (95% CI, 0.2% - 38.5%). Four (4) patients achieved PD (Progressive disease) in terms of the investigator-assessed best overall response per RECIST guideline ver. 1.1. Their PDs were not considered pseudoprogression at the time of confirmed response; therefore, response evaluation per iRECIST was not performed. As for the investigator-assessed best local response, no patients achieved L-CR (Local complete response), and the L-CR rate was 0% (95% CI, 0.0% - 26.5%). The median L-PFS (Local progression-free survival) was 4.0 months (95% CI, 2.6 - 5.7 months), the median PFS (Progression-free survival) was 2.1 months (95% CI, 1.0 - 2.4 months), and the median OS (Overall survival) was 5.7 months (95% CI, 2.6 - 9.1 months). In the Dose escalation part, the number of patients who achieved either CR or PR in terms of the investigator-assessed best overall response per RECIST guideline ver. 1.1 was 1 patient (who achieved PR). As for the investigator-assessed best local response, no patients achieved L-CR. The L-PFS ranged from 0.7 to 13.4 months, PFS ranged from 0.7 to 13.4 months, and the OS ranged from 0.7 to 29.5 months. Safety results: In the combination therapy with an anti-PD-1 antibody drug (nivolumab) and PIT using the investigational drug of ASP-1929, no new safety concerns were raised under 100J/cm2 determined as the RD (Recommended dose) for energy density of laser illumination. For details, refer to [Adverse events].

The combination therapy with an anti-PD-1 antibody drug (nivolumab) and PIT using the investigational drug of ASP-1929 raised no new safety concerns in patients with unresectable advanced/recurrent gastric cancer. As for efficacy, it is considered limited and further investigation is necessary, including pre- and post-treatment development of EGFR and biomarker measurements.

No

Kohei Shitara

National Cancer Center Hospital East

6-5-1,Kashiwanoha,Kashiwa,Chiba,277-8577,Japan

GE_PIT_core@east.ncc.go.jp

Kohei Shitara

National Cancer Center Hospital East

6-5-1,Kashiwanoha,Kashiwa,Chiba,277-8577,Japan

+81-4-7133-1111

GE_PIT_core@east.ncc.go.jp

completed

Nov. 01, 2019

Interventional

open-label, single-arm Phase Ib study

treatment purpose

1

Inclusion criteria including below but not limited to:
1) Patients with unresectable advanced/recurrent gastric cancer or esophageal cancer that progressed after chemotherapy. This also includes locally advanced cancer.
2) Patients with histologically or cytologically confirmed squamous cell carcinoma or adenocarcinoma. Patients with confirmed EGFR-positive if adenocarcinoma.
3) Patients with illuminable primary tumor.
4) Patients with a measurable lesion according to RECIST guideline ver.1.1.
5) Patients aged over 20 years at the time of consent obtaining.
6) Patients applicable to either 0 or 1 in ECOG performance status (PS) within 14 days prior to enrollment.
7) Patients who are judged to have sufficient organ functions based on the laboratory values measured within 14 days before enrollment.
8)Patients with recovered toxicity to CTCAE Grade 1 or lower from prior treatment. Alopecia, peripheral sensory neuropathy, skin hyperpigmentation and dysgeusia are excluded.
9)Patients received no blood transfusion or no hematopoietic factor preparations including granulocyte-colony-stimulating factor (G-CSF) within 7 days prior to enrollment.
10) Female patients with childbearing potential must be negative for pregnancy test performed within 7 days prior to enrollment.
11) Patients agreed to use adequate contraceptive method during the protocol treatment period and for 6 months after discontinuation of the protocol treatment.
12) Patients with possibility for 3 months or more of survival from the protocol treatment initiation date.
13) Patients whose consent for participation in this study is obtained by a written document by him/herself.

Exclusion criteria including below but not limited to:
1) Patients determined for a presence of multiorgan invasions of primary tumor.
2) Patients received systemic chemotherapy, anti-PD-1/PD-L1 antibody drug, radiotherapy, surgical operation or hormone therapy within 2 weeks prior to enrolment.
3) Patients received cancer treatment vaccine, treatment with genetically modified virus including virus lytic treatment or genetically modified cellular therapy within 4 weeks prior to enrolment.
4) Patients with serious cardiovascular diseases (congestive heart failure of class 3 or higher in NYHA classification occurred within 6 months prior to enrolment, history of unstable angina or myocardial infraction, or complication with serious arrhythmia).
5) Patients required administration of systemic corticosteroid or immunosuppressant.
Patients receiving hormone replacement therapy (10 mg/day or less of prednisolone equivalent) are excluded.
6) Patients received live vaccine within 30 days prior to the protocol treatment.
7) Patients with complication from active infection that requires systemic treatment.
8) Patients with active multiple cancers. However, patients with asynchronous or synchronous multiple cancer who satisfies either of the following conditions is handled as eligible irrespective of the cancer type, disease stage and treatment history.
Systemic therapy (chemotherapy, immunotherapy, endocrine therapy, etc.) is not needed for at least 6 months after consent obtaining.
Complete cure can be expected with a local therapy such as endoscopic therapy.
9) Patients with complication with poorly controlled autoimmune disease or with history of chronic/recurrent autoimmune disease.
10) Patients with clinical symptoms or imaging findings of active interstitial pneumonia or pulmonary fibrosis.
11) Patients with positive in HIV-1 antibody testing, or who have active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Patients with positive in hepatitis B virus (HBV) or hepatitis C virus (HCV) testing, but who have adequate hepatic function and well-controlled disease are not excluded.
12) Patients with history of serious infusion reaction (Grade 3 or higher) against cetuximab.
13) Patients needing ophthalmological examination or surgical operation etc., in which exposure to strong light is foreseeable, within 4 weeks after administration of the investigational drug.
14) Pregnant or breastfeeding female patients.
15) Patients who are judged by the principal investigator as ineligible to be administered the investigational drug, or in whom the principal investigator judges that laser illumination cannot be performed safely.
16) Patients with a previous experience with using ASP-1929.

Both

unresectable advanced/recurrent gastric cancer or esophageal cancer

investigational material(s)
Generic name etc : ASP-1929
INN of investigational material : -
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Normally ASP-1929 shall be administered at the dose level of 640 mg/m2 by intravenous infusion taking approximately 2 hours.Laser shall be illuminated under endoscope approximately at 24hours after infusion of ASP-1929.

safety
efficacy
For only dose escalation part
1) Incidence rate of dose-limiting toxicity (DLT)

safety
efficacy
pharmacokinetics
For only dose escalation part
1) PKs of ASP-1929, cetuximab and IRDye 700DX
2) ADA development
For both dose escalation part and expansion part
3) Incidence rate of adverse event (incidence rate of adverse event determined according to CTCAE Version 5.0)
4) Objective response rate determined by the principal investigator or sub-investigator based on RECIST ver. 1.1
5) Objective response rate determined by the principal investigator or sub-investigator based on iRECIST
6) Local complete response (L-CR) rate determined by the principal investigator or sub-investigator
7) Local progression-free survival (L-PFS)
8) Progression-free survival (PFS)
9) Overall survival (OS)
10)Incidence rate of device deficiencies (medical devices)

+81-4-7133-1111

Sept. 18, 2019