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A Phase 1/1b Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of JNJ-63723283, an Anti-PD-1 Monoclonal Antibody, as Monotherapy or in Combination With Erdafitinib in Japanese Subjects With Advanced Solid Cancers

A Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of JNJ-63723283, an Anti-Programmed Cell Death (PD)-1 Monoclonal Antibody, as Monotherapy or in Combination With Erdafitinib in Japanese Participants With Advanced Solid Cancers

22

Baseline characteristics were assessed on all treated analysis set population defined as of all enrolled participants (22 participants) who received at least 1 dose of study intervention. In both phases of the study, the baseline characteristics were comparable between cohorts in each part. A higher proportion of participants (>=50%) were male and all were Asian (Japanese). The median age of participants was 66 years (range: 43 to 71 years) in Phase 1a and 68 years (range: 45 to 76 years) in Phase 1b. Median time from initial diagnosis to first dose was 23.4 months and 31.5 months in Phase 1a and Phase 1b, respectively.

A total of 22 participants were enrolled in the study (All treated analysis set consist of all enrolled subjects who received at least 1 dose of study intervention), out of which 9 participants were enrolled in Phase 1a and 13 participants were enrolled in Phase 1b. In Phase 1a, the 3 dose escalation cohorts enrolled 3 participants per cohort; and in Phase 1b, the 2 dose cohorts enrolled 13 participants (7 participants in cetrelimab [JNJ-63723283] 240 mg every 2 weeks (Q2W) + erdafitinib 6 mg and 6 participants in cetrelimab 240 mg Q2W + erdafitinib 8 mg). In Phase 1a, all participants discontinued the study intervention and were terminated from the study. The most common reason for study intervention discontinuation was progressive disease (PD) (8 participants), 1 participant discontinued due to a serious Grade 3 treatment-related AE of hepatic impairment. In Phase 1b, 3 (2 participants in cetrelimab 240 mg Q2W + erdafitinib 6 mg cohort, and 1 participant in JNJ-63723283 240 mg Q2W + erdafitinib 8 mg cohort) participants died during the study and were considered as study completers. Remaining 10 participants discontinued the study intervention and were terminated from the study. The reasons for study intervention discontinuation were PD (7 participants), and lost to follow-up, withdrawal by participant or start the next treatment (1 participant each).

AE was assessed on all treatment analysis set defined as all enrolled subjects who received at least 1 dose of study intervention. Phase 1a: TEAEs were reported in 8 participants (88.9%) and these TEAEs were treatment-related in 6 participants (66.7%) The most common treatment-emergent AEs (TEAE)s in Phase 1a (cetrelimab administered alone) were rash 44.4%, constipation, nausea, stomatitis, vomiting, pyrexia, decreased appetite, and cough (22.2% each). None of the participants had TEAE that led to death. Serious TEAEs were reported for 3 participants (33.3%), among which 2 participants (22.2%) had treatmentrelated serious TEAE. These SAEs included fulminant type 1 diabetes mellitus (Grade >=3; treatment-related), hepatic function abnormal (Grade >=3; treatment-related) and decreased appetite (Grade >=3; not treatmentrelated). Grade 3 or higher TEAEs were reported in 4 participants (44.4%), among which 2 participants (22.2%) had treatment related Grade 3 or higher TEAEs. TEAEs leading to drug interruption were reported for 2 participants (22.2%) among which 1 participant (11.1%) had the treatment-related TEAE leading to drug interruption. One participant (11.1%) had TEAE of Grade 3 abnormal hepatic function leading to drug discontinuation, and this participant had at least 1 TEAE that was reported as treatment-related. Treatment-emergent irAEs were reported for 4 participants (44.4%). The median time to onset of first irAE was 86 days and the median time of duration of first irAE was 145 days. No infusion related reactions (IRRs) were recorded. Phase 1b: TEAEs were reported in all 13 participants (100.0%). The most common TEAEs in Phase 1b (cetrelimab administered along with erdafitinib) were hyperphosphatemia (84.6%), diarrhea (61.5%), stomatitis, decreased appetite, blood creatinine increased (38.5% each), nausea, vomiting, ALT increased, lipase increased, anemia (30.8% each), AST increased, blood ALP increased, gamma-glutamyltransferase (GGT) increased, nail discoloration, and dysgeusia (23.1%). 8 participants (61.5%) had at least 1 TEAE related to cetrelimab, and all 13 participants had at least 1 TEAE related to erdafitinib. One participant (7.7%) from cetrelimab 240 mg Q2W + erdafitinib 6 mg cohort had at least 1 TEAE (completed suicide) that led to death, but this TEAE was not related to study intervention. Two participants died within the follow-up due to PD. Serious TEAEs were reported for 5 participants (38.5%) among which 2 participants (15.4%) had treatmentrelated serious TEAE. These SAEs included decreased appetite (Grade 2; treatment-related), Stevens-Johnson syndrome (Grade >=3; treatment-related), tumor pain (Grade >=3; not treatment-related), intracranial hemorrhage (Grade 2; not treatment-related), completed suicide (Grade >=3; not treatment-related), bronchial obstruction (Grade >=3; not treatment-related) and hiatus hernia (Grade >=3; not treatmentrelated). Grade 3 or higher TEAEs were reported for 7 participants (53.8%) among which 3 participants (23.1%) had treatment-related Grade 3 or higher TEAEs. TEAEs leading to erdafitinib dose reduction were reported for 5 participants (38.5%) and all 5 participants had at least 1 treatment-related TEAE leading to erdafitinib dose reduction. TEAE leading to erdafitinib dose reduction that occurred in >=2 participants was paronychia (2 participants, 15.4%). >= Grade 3 TEAEs leading to erdafitinib dose reduction included ALT increased and AST increased events (1 participant each, 7.7% each). Both these events were considered as treatment-related. TEAEs leading to any drug interruption were reported for 8 participants (61.5%) among which 6 participants (46.2%) had treatment related TEAE leading to any drug interruption. 2 participants (15.4%) had TEAE leading to any drug discontinuation among which 1 participant (7.7%) had at least one TEAE that was reported as treatment related. Treatment-emergent irAEs were reported in 2 participants (15.4%). The median time to onset of first irAE was 66 days and the median time of duration of first irAE was 68 days. No IRRs were recorded.

Primary Safety Endpoints Safety assessments were based on all treated analysis set, defined as all enrolled subjects who received at least 1 dose of study intervention. Phase 1a and Phase 1b: Number and Severity of Participants with DLTs No DLTs were reported in Phase 1a. One participant (8.3%) who received cetrelimab 240 mg Q2W + erdafitinib 6 mg had one DLT which was a serious, treatment-related, Grade 3 Steven-Johnson syndrome in Phase 1b.

Secondary Safety Endpoints Phase 1a and Phase 1b: Number of Participants with AEs and irAEs by Severity Phase 1a: Eight participants (88.9%) experienced at least 1 TEAE, out of which, 6 participants (66.7%) had at least 1 treatment-related TEAE. Treatment-emergent irAEs were reported for 4 participants (44.4%). Phase 1b: All 13 participants (100.0%) experienced at least 1 TEAE and all participants had at least 1 treatmentrelated TEAE. Treatment-emergent irAEs were reported in 2 participants (15.4%). Phase 1a and Phase 1b: Number of Participants With Clinically Significant Changes in Vital Signs as a Measure of Safety and Tolerability Phase 1a: Vital signs showed no clinically meaningful changes in majority of the participants. Three participants had clinically important changes in the vital signs. Phase 1b: Vital signs showed no clinically meaningful changes in majority of the participants. Five participants had clinically important changes in the vital signs. Phase 1a and Phase 1b: Number of Participants WithECG Abnormalities as a Measure of Safety and Tolerability Phase 1a: ECG showed no clinically meaningful changes in majority of the participants. Echocardiography was performed only at screening in all participants. None of the participants had an average QTcF or QTcB values that exceeded 480 millisecond (msec) post-baseline, and an average change from baseline in QTcF or QTcB did not exceed 60 msec. Phase 1b: ECG showed no clinically meaningful changes in majority of the participants. Echocardiography was performed only at screening in all participants. None of the participants had an average QTcF or QTcB values that exceeded 480 msec post-baseline, and an average change from baseline in QTcF or QTcB did not exceed 60 msec. Phase 1a and Phase 1b: Number of Participants With Clinical Laboratory Abnormalities as a Measure of Safety and Tolerability Phase 1a: The clinical laboratory data showed no clinically meaningful changes in majority of the participants. No Grade 3 or Grade 4 hematology abnormal parameters were recorded. 3 participants had Grade 3 or Grade 4 clinical chemistry abnormal values post-baseline. One participant had abnormal endocrine parameter which was reported as an AE. Phase 1b: The clinical laboratory data showed no clinically meaningful changes in majority of the participants. No Grade 4 hematology parameters were recorded. Grade 3 lymphocyte count decreased in 4 participants during the study. Post-baseline markedly abnormal clinical chemistry laboratory values were recorded for 1 participant with alanine aminotransferase (ALT)>5 x upper limit of normal ULN and 3 participants with aspartate aminotransferase (AST) >3 x ULN). Hyperphosphatemia isa class effect of fibroblast growth factor receptor (FGFR) inhibitors (erdafitinib), and was experienced by 11 participants, however, none of these were Grade 3 or higher. Three participants had Grade 3 or Grade 4 clinical chemistry values post-baseline. 2 participants had abnormal endocrine parameters which were reported as AEs. Secondary Pharmacokinetic (PK) Endpoints Pharmacokinetic parameters were assessed based on PK analysis set defined as subjects who have received at least 1 dose of study intervention and have at least 1 evaluable concentration data of cetrelimab for Phase 1a part, and cetrelimab or erdafitinib for part 1b for PK analysis. Phase 1a and Phase 1b: Serum Concentration of Cetrelimab After single IV infusion of cetrelimab, mean Cmax and AUC2wk were 27.5 microgram per millilitre (microg/mL) and 4576 microg.h/mL for cetrelimab 80 mg and 83.8 microg/mL and 13578 microg.h/mL for cetrelimab 240 mg. Systemic exposure (Cmax, AUC2wk) increased 3-fold with the dose increasing 3-fold as well. After single IV infusion of cetrelimab 240 mg in combination with oral administration of 6 mg and 8 mg erdafitinib, comparable mean Cmax values of 82.4 microg/mL and 89.6 microg/mL, respectively, were observed. Median Tmax, mean Cmax, AUC2wk, and Ctrough at Cycle 1 Day 15 appeared to be comparable for the single IV infusion of cetrelimab 240 mg alone and the single IV infusion of cetrelimab 240 mg in combination with erdafitinib. Phase 1b: Plasma Concentration of Erdafitinib After daily oral administration of 6 mg and 8 mg erdafitinib in combination with IV administration of cetrelimab 240 mg, mean plasma total erdafitinib concentrations were higher for the 8 mg dose. Mean total erdafitinib Ctrough values for both erdafitinib doses appeared to reach maximum values somewhere at Cycle 1 Day 15. After daily oral administration of 6 mg and 8 mg erdafitinib in combination with IV administration of cetrelimab 240 mg, mean unbound fractions erdafitinib appeared to be comparable for both doses up to Cycle 1 Day 2. From Cycle 1 Day 15, the mean unbound fraction erdafitinib appeared to be higher for the 8 mg dose although ranges were overlapping for both doses. Secondary Immunogenicity Endpoint: Immunogenicity was assessed on the immunogenicity analysis set defined as subjects who have received at least 1 dose of study intervention and have appropriate serum sample for antibodies to cetrelimab detection. Proportion of Participants with Antibodies to Cetrelimab In Phase 1a, none of the participants had positive samples for anti-cetrelimab antibodies. In Phase 1b, 1 participant had a positive sample for anti-cetrelimab antibodies with a titer of 6400 at baseline but all had negative sample for treatment-induced antibodies to cetrelimab.

The RP2D of cetrelimab, alone or with erdafitinib, was determined from Phase 1a and Phase 1b safety data. Japanese RP2Ds align with Global RP2Ds from studies 63723283LUC1001 and 42756493BLC2002. Cetrelimab's safety profile was consistent with PD-1 safety antagonist profiles and aligns with other studies. After cetrelimab IV infusion (80 mg, 240 mg, 480 mg), mean serum concentrations increased with dose. In Phase 1a, no anti-cetrelimab antibodies were detected; Phase 1b had one positive result.

June. 12, 2024

June. 04, 2024

https://doi.org/10.1007/s10637-024-01433-3

No

Janssen Pharmaceutical K.K., Japan

Janssen Pharmaceutical K.K., Japan

電話番号 0120-183-275 FAX番号 0120-275-831 受付時間 9：00～17：40（土・日・祝日および会社休日を除く）

completed

Oct. 01, 2018

Interventional

Parallel Assignment

treatment purpose

1

- Radiographically, histologically, or cytologically confirmed advanced or refractory solid tumor(s) that is metastatic or unresectable, and previously received or was ineligible for standard treatment option. Participants with solid tumor(s) for which anti-PD-1 or anti-PD-L1 antibody as a monotherapy is approved in Japan are eligible.

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Thyroid function laboratory values within normal range

- A woman must be:
a) Not of childbearing potential;
b) Of childbearing potential and practicing a highly effective, preferably user-independent method of contraception (failure rate of less than (<) 1 percent (%) per year when used consistently and correctly) and agrees to remain on a highly effective method while receiving study intervention and continue for 5 months following discontinuation of JNJ-63723283 or 3 months following discontinuation of erdafitinib, whichever is longer. Especially participants receiving erdafitinib must agree to use two contraceptive methods and one must be user-independent method;
c) Agree not to donate eggs (ova, oocytes), during the study and continue for 5 months following discontinuation of JNJ-63723283 or 3 months following discontinuation of erdafitinib, whichever is longer

- A male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person and must agree not to donate sperm for 5 months following discontinuation of JNJ-63723283 or 5 months following discontinuation of erdafitinib, whichever is longer

- Had prior treatment with an anti-PD-1 antibody, anti-PD-L1 antibody or anti-PDL2 antibody within 30 days of first study drug administration and/or has an ongoing Grade 2 or higher immunotherapy-related toxicity. If the subject has an experience of treatment with these agents, the subject must not have had severe immunotherapy-related toxicity

- History of or concurrent interstitial lung disease

- Active autoimmune disease or a documented history of autoimmune disease that requires systemic steroids or immunosuppressive agents

- Grade 3 or higher toxicity effects from previous treatment with immunotherapy

- Has taken immunosuppressive doses of systemic medications, such as corticosteroids doses greater than (>) 10 milligram per day (mg/day) prednisolone or equivalent), within 2 weeks before the planned first dose of study drug

Both

Neoplasm

investigational material(s)
Generic name etc : JNJ-63723283/ Cetrelimab
INN of investigational material : -
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Phase 1a: JNJ-63723283 (Monotherapy) Participants will receive monotherapy of JNJ-63723283 intravenously. The subsequent dose levels of JNJ-63723283 will be escalated using Bayesian logistic regression model (BLRM).

control material(s)
Generic name etc : Erdafitinib
INN of investigational material : -
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Phase 1b: Erdafitinib Combination Participants will receive erdafitinib in combination with JNJ-63723283 which will be escalated using BLRM.

safety
Phase 1a and Phase 1b: Number of Participants with Dose Limiting Toxicity (DLT)
Up to 6 weeks (maximum)
safety
Phase 1a and Phase 1b: Severity of DLT as Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)
Up to 6 weeks (maximum)

safety
Phase 1b: Number of Participants with Adverse Events and Immune-Related Adverse Event (irAE) by Severity

Approximately up to 3 years
safety
Phase 1a and Phase 1b: Number of Participants With Clinically Significant Changes in Vital Signs as a Measure of Safety and Tolerability
Approximately up to 3 years
safety
Phase 1a and Phase 1b: Number of Participants With Clinical Laboratory Abnormalities as a Measure of Safety and Tolerability
Approximately up to 3 years
safety
Phase 1a and Phase 1b: Number of Participants With ECG Abnormalities as a Measure of Safety and Tolerability
Approximately up to 3 years
pharmacokinetics
Phase 1a and Phase 1b: Maximum Serum Concentration (Cmax) of JNJ-63723283
Approximately up to 3 years
pharmacokinetics
Phase 1a and Phase 1b: Serum Concentration Immediately Prior to the Next Drug Administration (Ctrough) of JNJ-63723283
Approximately up to 3 years
pharmacokinetics
Phase 1a and Phase 1b: Time to reach Maximum Observed serum Concentration (Tmax) of JNJ-63723283
Approximately up to 3 years
pharmacokinetics
Phase 1a and Phase 1b: Area Under the Serum Concentration-Time
Curve Between 2 Defined Sampling Points, (t1 and t2) (AUC[t1-t2]) of JNJ-63723283
Approximately up to 3 years
pharmacokinetics
Phase 1a and Phase 1b: Elimination Half-Life (t1/2) of JNJ-63723283

Approximately up to 3 years
pharmacokinetics
Phase 1a and Phase 1b: Total Systemic Clearance (CL) of JNJ-63723283
Approximately up to 3 years
pharmacokinetics
Phase 1a and Phase 1b: Volume of Distribution at Steady-State (Vss) of JNJ-63723283
Approximately up to 3 years
pharmacokinetics
Phase 1b: Cmax of Erdafitinib
Approximately up to 3 years
pharmacokinetics
Phase 1b: Ctrough of Erdafitinib
Approximately up to 3 years
pharmacokinetics
Phase 1a and Phase 1b: Numb+H62+H63
Approximately up to 3 years

Aug. 06, 2018