A Phase I Dose Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Ipilimumab in Chinese Patients with Select Advanced Solid Tumors

Abstract

Lessons Learned

• The overall safety profiles of ipilimumab 3 mg/kg and 10 mg/kg administered every 3 weeks, were consistent between Chinese patients with solid tumors in the current study and patients from previous U.S. ipilimumab monotherapy studies. No new safety signals were identified.

• The mean systemic exposures to ipilimumab (assessed by first dose area under the curve during the dosing interval and maximum serum concentration) were numerically lower in the Chinese patient population than in U.S. patients for both 3 mg/kg and 10 mg/kg doses; however, the range of serum concentrations in the Chinese and U.S. populations overlapped (3 mg/kg and 10 mg/kg), suggesting that ipilimumab pharmacokinetics was ethnically insensitive in this study.

Background

This phase I, open‐label study assessed ipilimumab safety, tolerability, pharmacokinetics (PK), immunogenicity, and antitumor activity in Chinese patients with unresectable, metastatic, recurrent malignant melanoma (MM) or nasopharyngeal carcinoma (NPC).

Methods

Of 39 patients enrolled, 25 received ipilimumab (11 patients received 3 mg/kg, and 14 patients received 10 mg/kg). Reasons for not receiving treatment were withdrawal of consent (3 patients), no longer meeting the criteria (10 patients), and one recorded as “other.” During the induction phase, patients received ipilimumab (3 mg/kg, i.v.), on day 1 of a 3‐week cycle, to a maximum of four doses or progressive disease (PD). During the maintenance phase at week 24, patients received ipilimumab (3 mg/kg, i.v.) on day 1 of a 12‐week cycle, to a maximum of 3 years or PD. Considering the co‐primary safety and PK endpoints, the successive dosing required nine patients with two or fewer dose‐limiting toxicities during the 42‐day observation period to proceed with a new cohort of nine patients at 10 mg/kg.

Results

Ipilimumab safety and PK profiles were similar in Chinese and predominantly White populations. Ipilimumab was well tolerated. Most adverse events (AEs) were grades 1–2 and experienced by 11 patients treated with 3 mg/kg and 14 patients treated with 10 mg/kg. There were no new safety concerns. Incidence of anti‐ipilimumab antibodies was low (1 of 10 in the 3 mg/kg patients and 2 of 13 in the 10 mg/kg patients) and without safety implications. In the 3 mg/kg group, 8 of 11 patients had PD. In the 10 mg/kg group (all NPC, 0 MM patients), 11 of 14 patients had PD. Three patients had stable disease (one at 3 mg/kg and two at 10 mg/kg).

Conclusion

Ipilimumab was well tolerated in Chinese patients, showing similar safety and PK to previous studies in predominantly White populations.

Discussion

Ipilimumab is a human monoclonal antibody that binds CTLA‐4, a T‐cell negative regulator, preventing ligand interaction on antigen‐presenting cells [1]. It is approved treatment of advanced melanoma in >45 countries (3 mg/kg) and in the U.S. for melanoma adjuvant therapy (10 mg/kg) and unresectable or metastatic melanoma (3 mg/kg) [2]. Prognosis with metastatic/refractory solid tumors is poor, with an unmet medical need [3, 4]. Evidence for the safety, tolerability, and PK of ipilimumab is based on predominantly White population study data [5].

This phase I, open‐label study assessed the safety, tolerability, and PK of ipilimumab in Chinese patients with unresectable, metastatic, recurrent MM or NPC. Secondary objectives were immunogenicity and preliminary antitumor activity.

There were three study phases: screening (up to 28 days), treatment (induction and maintenance), and clinical follow‐up (90 days). During the induction phase, subjects received ipilimumab (i.v.) on day 1 of each cycle, every 3 weeks, up to four doses or until PD. During the maintenance phase, subjects received ipilimumab (i.v.) on day 1 of each cycle, every 12 weeks, starting at week 24 up to PD, for a maximum of 3 years from first dose.

Nine subjects were initially treated (3 mg/kg); no more than two subjects experienced dose‐limiting toxicities (DLTs) during the 42‐day observation period, so a new cohort of nine patients was treated at 10 mg/kg (this would have been increased to 18 patients if DLTs were experienced by three or more patients at 3 mg/kg). After determining the maximum tolerated/administered dose, additional patients were enrolled to have at least 10 per group with PK samples. Primary endpoints were AEs, serious AEs, AEs leading to discontinuation/death, and pharmacokinetic parameters of ipilimumab, including maximum serum concentration (C_max), time to achieve C_max (T_max), trough concentration (C_trough), and area under the curve from 0 to 21 days (AUC_{0–21 days}). Secondary endpoints were best overall response, duration of response, progression‐free survival, and immunogenicity. Descriptive statistics were used to summarize continuous variables, and percentages/frequencies were used for categorical variables.

Safety profiles and cross‐dose comparisons were similar in Chinese patients (n = 25) and prior U.S. studies with ipilimumab (>94% White). There were no new safety signals, drug‐related deaths, or drug‐related serious adverse events (SAEs) during this study (Table 1: All 25 patients had AEs: 11 patients 3 mg/kg; 14 patients 10 mg/kg ipilimumab). Most AEs affected the skin, gastrointestinal tract, endocrine system, or liver and were grades 1–2. Eleven patients had adverse drug reactions (ADRs) in each group; Only one ADR led to discontinuation (3 mg/kg: hypothyroidism, NPC). Ipilimumab was well tolerated (one dose‐limiting toxicity: erythema; 10 mg/kg, NPC).

First dose area under the curve during the dosing interval and C_max increased dose‐proportionally (Fig. 1A). Mean ipilimumab exposures for both doses were lower in Chinese versus U.S. patients. Serum concentrations in these populations overlapped, with both doses, indicating that ipilimumab PK was ethnically insensitive in this study (Fig. 1B and C).

Figure 1.

Comparison of ipilimumab concentration‐time profiles and pharmacokinetic parameters in Chinese and U.S. patients at 3 and 10 mg/kg. (A): Geometric mean ipilimumab serum concentration‐time profile and pharmacokinetic (PK) parameters: 3 mg/kg and 10 mg/kg. (B): Comparison of data obtained in Chinese and U.S. study participants: Mean ipilimumab serum concentration‐time profile and PK parameters after single dose (3 mg/kg). (C): Comparison of data obtained in Chinese and U.S. study participants: Mean ipilimumab serum concentration‐time profile and PK parameters after single dose (10mg/kg).

Abbreviations: AUC, area under the curve; C_max, maximum concentration; CV, coefficient of variation.

Incidence of anti‐ipilimumab antibodies did not affect safety and was low (1/10 patients in the 3 mg/kg group; 2/13 patients in the 10 mg/kg group). In the 3 mg/kg group, five of six patients with MM had PD and one of six was not evaluable (NE), and three of five patients with NPC had PD, one of five was NE, and one of five had stable disease (SD). In the 10 mg/kg group (all with NPC, 0 MM), 11 of 14 patients had PD, 2 of 14 had SD, and 1 of 14 was NE.

Previous studies, conducted predominantly in White patients, have indicated that ipilimumab is safe and well tolerated. This study confirmed these findings in Chinese patients with MM/NPC and demonstrated similar PK between the study populations.

Trial Information

Disease	Advanced cancer/solid tumors
Stage of Disease/Treatment	Metastatic/advanced or recurrent disease
Prior Therapy	No designated number of regimens
Type of Study	Phase I, dose evaluation and cohort expansion
Primary Endpoints	Safety, tolerability and pharmacokinetics
Secondary Endpoints	Immunogenicity and preliminary antitumor activity
Additional Details of Endpoints or Study Design
Dose evaluation and cohort expansion phases: Based on clinical experience in a predominantly White population, ipilimumab safety, tolerability, and PK were assessed in Chinese patients with advanced/recurrent solid tumors. Patients started an induction phase of 3 mg/kg ipilimumab (i.v., day 1 of a 3‐week cycle, repeated up to four times or until progressive disease). Maintenance phase started at week 24 (i.v., day 1 of a 12‐week cycle), continuing up to 3 years from first dose, dependent on disease. The successive ascending dose (10 mg/kg) was administered by a 9 + 9 design.
Investigator's Analysis
Drug tolerable; efficacy was not fully evaluable due to limited patient numbers, warranting exploration in a larger study of patients with malignant melanoma and nasopharyngeal carcinoma.

Drug Information

Generic/Working Name	Ipilimumab
Trade Name	Yervoy®
Company Name	Bristol‐Myers Squibb Pharmaceuticals Ltd.
Drug Type	Antibody
Drug Class	Immune therapy
Dose	Induction: 3 mg/kg every 3 weeks; maintenance: 3 mg/kg every 12 weeks, 10 mg/kg every 12 weeks milligrams (mg) per kilogram (kg)
Route	i.v.
Schedule of Administration
Induction phase of 3 mg/kg ipilimumab (i.v., day 1 of a 3‐week cycle, repeated up to four times or until progressive disease). Maintenance phase started at week 24 (i.v., day 1 of a 12‐week cycle), continuing to 3 years from first dose, dependent on disease. The successive ascending dose (10 mg/kg) was administered by a 9 + 9 design.

Dose Escalation Table

Dose level	Dose of drug	Number enrolled	Number evaluable for toxicity
Malignant melanoma	3 mg/kg	6	6
Nasopharyngeal carcinoma	3 mg/kg	5	5
Nasopharyngeal carcinoma	10 mg/kg	14	14

Dose Information – All Treated Patients

	Ipilimumab 3 mg/kg	Ipilimumab 10 mg/kg
N	11	14
Malignant melanoma (n)	6	0
Number of doses	4.0 (3–4)	0
Duration of therapy (weeks)	12.1 (8.3–12.7)	0
Cumulative dose per patient (mg/kg)	11.9 (9.0–12.3)	0
Nasopharyngeal carcinoma (n)	5	14
Number of doses	4.0 (1–5)	3.5 (1–6)
Duration of therapy (weeks)	12.0 (3.0–32.1)	10.5 (3.0–38.0)
Cumulative dose per patient (mg/kg)	11.7 (3.0–15.3)	35.1 (10.0–58.8)

Data represent median (range).

Patient Characteristics: All Treated Patients

Number of Patients, Male	18 (72%)
Number of Patients, Female	7 (28%)
Stage	Advanced (stage 3 or 4 at study entry)
Age	Median (range): 48 (23–68) years
Number of Prior Systemic Therapies
Patients with malignant melanoma: One regimen: two patients (33.3%). Two regimens: one patient (16.7%). Three regimens: one patient (16.7%). Four or more regimens: two patients (33.3%). Patients with nasopharyngeal carcinoma: One regimen: two patients (10.5%). Two regimens: two patients (10.5%). Three regimens: five patients (26.3%). Four or more regimens: 10 patients (52.6%).
Performance Status: ECOG	0 : 11 patients 1 : 14 patients
Other	Race: Asian, 100%. Complete baseline demographic and disease characteristics are presented in Table 2.
Cancer Types or Histologic Subtypes	Malignant melanoma, 6 (24% of patients). Nasopharyngeal carcinoma, 19 (76% of patients).

Table 2.

Baseline patient characteristics and prior cancer therapy

Characteristics	Ipilimumab 3 mg/kg (n = 11), n (%)	Ipilimumab 10 mg/kg (n = 14), n (%)	Total (n = 25), n (%)
Age, median (range)	44 (23, 68)	48 (23, 57)	48 (23, 68)
Male	8 (73)	10 (71)	18 (72)
Race: Chinese	11 (100)	14 (100)	25 (100)
Weight, kg, median (range)	64.3 (47.9, 88.1)	58.2 (44.1, 78.4)	63.2 (44.1, 78.4)
ECOG status
0	6 (55)	5 (36)	11 (44)
1	5 (45)	9 (64)	14 (56)
Tumor type
MM	6 (55)	0	6 (24)
Stage 3 disease status at study entry	1 (17)	0	1 (17)
Stage 4 disease status at study entry	5 (83)	0	5 (83)
NPC	5 (45)	14 (100)	19 (76)
Stage 3 disease status at study entry	0	1 (7)	1 (5)
Stage 4 disease status at study entry	5 (100)	13 (93)	18 (95)
Prior surgery
MM	6 (55)	0	6 (55)
Yes	6 (100)	0	6 (100)
No	0	0	0
NPC	5 (45)	14 (100)	19 (76)
Yes	4 (80)	13 (93)	17 (90)
No	1 (20)	1 (7)	2 (10)
Prior radiotherapy
MM	6 (55)	0	6 (24)
Yes	3 (50)	0	3 (50)
No	3 (50)	0	3 (50)
NPC	5 (45)	14 (100)	19 (76)
Yes	4 (80)	12 (86)	16 (84)
No	1 (20)	2 (14)	3 (16)
Prior systemic therapy, number of regimens
MM	6 (55)	0	6 (55)
1	2 (33)	0	2 (33)
2	1 (17)	0	1 (17)
3	1 (17)	0	1 (17)
≥4	2 (33)	0	2 (33)
NPC	5 (45)	14 (100)	19 (76)
1	1 (20)	1 (7)	2 (11)
2	1 (20)	1 (7)	2 (11)
3	0	5 (36)	5 (26)
≥4	3 (60)	7 (50)	10 (53)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; MM, malignant melanoma; NPC, nasopharyngeal carcinoma.

Primary Assessment Method

Title	Total Patient Population
Number of Patients Screened	39
Number of Patients Enrolled	39
Number of Patients Evaluable for Toxicity	25
Number of Patients Evaluated for Efficacy	25
Evaluation Method	RECIST version 1.1
Response Assessment CR	n = 0 (0%)
Response Assessment PR	n = 0 (0%)
Response Assessment SD	n = 3 (12%)
Response Assessment PD	n = 19 (76%)
Response Assessment OTHER	n = 3 (12%)
Outcome Notes
Objective response rate: n = 0 (0%). Disease control rate: n = 3 (12%). Enrolled and screened with signed informed consent within 28 days of first dose. Of the enrolled patients, 14 did not enter the treatment period: 10 no longer met the criteria, 3 withdrew informed consent, and 1 withdrew for other reasons; Other: Responses could not be determined for these patients.

Adverse Events of Special Interest, All Cycles

Name	NC/NA, %	Grade 1, %	Grade 2, %	Grade 3, %	Grade 4, %	Grade 5, %	All grades, %
Pruritus	55	27	18	0	0	0	45
Rash	55	27	18	0	0	0	45
Aspartate aminotransferase increased	64	27	9	0	0	0	36
Nausea	73	27	0	0	0	0	27
Pyrexia	82	18	0	0	0	0	18
Vomiting	82	18	0	0	0	0	18
Dizziness	91	9	0	0	0	0	9
Emotional disorder	91	0	9	0	0	0	9
Fatigue	91	9	0	0	0	0	9
Flushing	91	9	0	0	0	0	9
Gastrointestinal disorder	91	9	0	0	0	0	9
Hyperthyroidism	91	9	0	0	0	0	9
Hypothyroidism	91	0	9	0	0	0	9
Pruritus generalized	91	9	0	0	0	0	9
Skin exfoliation	91	0	9	0	0	0	9
Somnolence	91	9	0	0	0	0	9
Thyroid disorder	91	9	0	0	0	0	9
Chest discomfort	91	9	0	0	0	0	9
Alanine aminotransferase increased	91	0	9	0	0	0	9
Pigmentation disorder	91	0	9	0	0	0	9
Asthenia	82	18	0	0	0	0	18
Pain	82	9	9	0	0	0	18
Mouth ulceration	91	9	0	0	0	0	9
Dreamy state	91	9	0	0	0	0	9

Adverse Events Legend

Data represent number (%) of patients with all related adverse events by worst grade, occurring between the first dose and 90 days after the last dose, of study therapy. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

Abbreviation: NC/NA, no change from baseline/no adverse event.

All Cause Serious Adverse Events (3mg/kg group)

Name	Grade	Attribution
Malignant neoplasm progression	5	Unrelated
Malignant neoplasm progression	5	Unrelated
Malignant neoplasm progression	5	Unrelated
Malignant neoplasm progression	5	Unrelated
Chest pain	2	Unrelated
Hyponatremia	4	Unrelated

Serious Adverse Events Legend

Data represent number (%) of patients with all cause serious adverse events by worst grade, occurring between the first dose and 90 days after the last dose of study therapy. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

All Related Adverse Events, All Cycles (10 mg/kg group)

Name	NC/NA, %	Grade 1, %	Grade 2, %	Grade 3, %	Grade 4, %	Grade 5, %	All grades, %
Pruritus	93	7	0	0	0	0	7
Fatigue	57	29	14	0	0	0	43
Hypothyroidism	72	21	7	0	0	0	28
Hyperthyroidism	93	7	0	0	0	0	7
Hyponatremia	93	7	0	0	0	0	7
Productive cough	93	7	0	0	0	0	7
Pharyngitis	93	7	0	0	0	0	7
Vomiting	93	7	0	0	0	0	7
Pyrexia	93	0	7	0	0	0	7
Granulocytosis	93	7	0	0	0	0	7
Blister	93	7	0	0	0	0	7
Erythema	93	0	0	7	0	0	7
Leukocytosis	93	7	0	0	0	0	7
Rash	93	0	7	0	0	0	7

Adverse Events Legend

Data represent number (%) of patients with all related adverse events by worst grade, occurring between the first dose and 90 days after the last dose, of study therapy. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

Abbreviation: NC/NA, no change from baseline/no adverse event.

All Cause Adverse Events (3 mg/kg)

All phases, All cycles				Grade			Total
	NC/NA, %	1	2	3	4	5
Ipilimumab 3 mg/kg (n = 11), n (%)
Pruritus	55	3 (27.3)	2 (18.2)	0	0	0	5 (45.5)
Rash	55	3 (27.3)	2 (18.2)	0	0	0	5 (45.5)
Aspartate aminotransferase increased	64	3 (27.3)	1 (9.1)	0	0	0	4 (36.4)
Constipation	64	1 (9.1)	3 (27.3)	0	0	0	4 (36.4)
Cough	64	3 (27.3)	1 (9.1)	0	0	0	4 (36.4)
Malignant neoplasm progression	64	0	0	0	0	4 (36.4)	4 (36.4)
Weight decreased	64	2 (18.2)	2 (18.2)	0	0	0	4 (36.4)
Anemia	73	0	3 (27.3)	0	0	0	3 (27.3)
Decreased appetite	73	2 (18.2)	1 (9.1)	0	0	0	3 (27.3)
Nausea	73	3 (27.3)	0	0	0	0	3 (27.3)
Asthenia	82	2 (18.2)	0	0	0	0	2 (18.2)
Blood lactate dehydrogenase	82	0	2 (18.2)	0	0	0	2 (18.2)
Dizziness	82	2 (18.2)	0	0	0	0	2 (18.2)
Hypokalemia	82	0	0	2 (18.2)	0	0	2 (18.2)
Hyponatremia	82	0	0	1 (9.1)	1 (9.1)	0	2 (18.2)
Hypoproteinemia	82	1 (9.1)	1 (9.1)	0	0	0	2 (18.2)
Pain	82	1 (9.1)	1 (9.1)	0	0	0	2 (18.2)
Pyrexia	82	2 (18.2)	0	0	0	0	2 (18.2)
Vomiting	82	1 (9.1)	1 (9.1)	0	0	0	2 (18.2)
Abdominal pain	91	0	1 (9.1)	0	0	0	1 (9.1)
Alanine aminotransferase increased	91	0	1 (9.1)	0	0	0	1 (9.1)
Blood alkaline phosphatase increased	91	1 (9.1)	0	0	0	0	1 (9.1)
Blood creatinine increased	91	1 (9.1)	0	0	0	0	1 (9.1)
Chest discomfort	91	1 (9.1)	0	0	0	0	1 (9.1)
Chest pain	91	0	1 (9.1)	0	0	0	1 (9.1)
Dreamy state	91	1 (9.1)	0	0	0	0	1 (9.1)
Electrocardiogram QT prolonged	91	1 (9.1)	0	0	0	0	1 (9.1)
Emotional disorder	91	0	1 (9.1)	0	0	0	1 (9.1)
Fatigue	91	1 (9.1)	0	0	0	0	1 (9.1)
Flushing	91	1 (9.1)	0	0	0	0	1 (9.1)
Gamma‐glutamyltransferase increased	91	0	1 (9.1)	0	0	0	1 (9.1)
Gastrointestinal disorder	91	1 (9.1)	0	0	0	0	1 (9.1)
Hyperkalemia	91	0	1 (9.1)	0	0	0	1 (9.1)
Hyperthyroidism	91	1 (9.1)	0	0	0	0	1 (9.1)
Hypothyroidism	91	0	1 (9.1)	0	0	0	1 (9.1)
Insomnia	91	0	1 (9.1)	0	0	0	1 (9.1)
Mouth ulceration	91	1 (9.1)	0	0	0	0	1 (9.1)
Neurotoxicity	91	1 (9.1)	0	0	0	0	1 (9.1)
Otitis media	91	1 (9.1)	0	0	0	0	1 (9.1)
Pain in extremity	91	0	1 (9.1)	0	0	0	1 (9.1)
Pigmentation disorder	91	0	1 (9.1)	0	0	0	1 (9.1)
Platelet count increased	91	1 (9.1)	0	0	0	0	1 (9.1)
Pneumonia	91	0	1 (9.1)	0	0	0	1 (9.1)
Productive cough	91	1 (9.1)	0	0	0	0	1 (9.1)
Pruritus generalised	91	1 (9.1)	0	0	0	0	1 (9.1)
Skin disorder	91	0	1 (9.1)	0	0	0	1 (9.1)
Skin exfoliation	91	0	1 (9.1)	0	0	0	1 (9.1)
Somnolence	91	1 (9.1)	0	0	0	0	1 (9.1)
Tachypnoea	91	0	1 (9.1)	0	0	0	1 (9.1)
Thyroid disorder	91	1 (9.1)	0	0	0	0	1 (9.1)
Urine abnormality	91	0	1 (9.1)	0	0	0	1 (9.1)

All Cause Adverse Events All Cycles (10 mg/kg group)

Name	NC/NA, %	Grade 1, %	Grade 2, %	Grade 3, %	Grade 4, %	Grade 5, %	All grades, %
Fatigue	57	29	14	0	0	0	43
Hypothyroidism	72	14	14	0	0	0	28
Anemia	79	14	7	0	0	0	21
Aspartate aminotransferase increased	79	14	0	7	0	0	21
Constipation	79	21	0	0	0	0	21
Hyponatremia	79	7	0	14	0	0	21
Weight decreased	79	14	7	0	0	0	21
Alanine aminotransferase increased	86	14	0	0	0	0	14
Back pain	86	0	14	0	0	0	14
Blood albumin decreased	86	7	7	0	0	0	14
Blood blister	86	14	0	0	0	0	14
C‐reactive protein increased	86	14	0	0	0	0	14
Hemangioma	86	14	0	0	0	0	14
Leukocytosis	86	7	7	0	0	0	14
Malignant neoplasm progression	86	0	0	0	0	14	14
Neutrophil count increased	86	7	7	0	0	0	14
Productive cough	86	7	7	0	0	0	14
Pruritus	86	14	0	0	0	0	14
Pyrexia	86	7	7	0	0	0	14
Rash	86	7	7	0	0	0	14
Vomiting	86	7	7	0	0	0	14
Arthralgia	93	7	0	0	0	0	7
Blister	93	7	0	0	0	0	7
Blood glucose increased	93	7	0	0	0	0	7
Blood lactate dehydrogenase increased	93	0	7	0	0	0	7
Capillary disorder	93	7	0	0	0	0	7
Chest pain	93	0	7	0	0	0	7
Decreased appetite	93	0	7	0	0	0	7
Dysphagia	93	0	0	7	0	0	7
Dyspnea exertional	93	0	7	0	0	0	7
Edema peripheral	93	7	0	0	0	0	7
Epistaxis	93	7	0	0	0	0	7
Erythema	93	0	0	7	0	0	7
Giingival bleeding	93	7	0	0	0	0	7
Granulocytosis	93	7	0	0	0	0	7
Hypercholesterolemia	93	7	0	0	0	0	7
Hyperthyroidism	93	7	0	0	0	0	7
Hyperuricemia	93	7	0	0	0	0	7
Hypoesthesia	93	0	0	7	0	0	7
Hypoalbuminemia	93	7	0	0	0	0	7
Increased viscosity of upper respiratory secretion	93	0	7	0	0	0	7
Lung infection	93	0	7	0	0	0	7
Lymphadenopathy	93	0	7	0	0	0	7
Muscle fatigue	93	7	0	0	0	0	7
Nausea	93	0	7	0	0	0	7
Otitis media	93	0	7	0	0	0	7
Pain	93	0	7	0	0	0	7
Paronychia	93	0	7	0	0	0	7
Peripheral sensorimotor neuropathy	93	0	0	7	0	0	7
Peripheral swelling	93	7	0	0	0	0	7
Pharyngitis	93	7	0	0	0	0	7
Pneumonitis	93	0	7	0	0	0	7
Pyelonephritis acute	93	7	0	0	0	0	7
Rhinorrhoea	93	7	0	0	0	0	7
Sensorimotor disorder	93	0	0	7	0	0	7
Sinusitis	93	7	0	0	0	0	7
Stomatitis	93	7	0	0	0	0	7

Adverse Events Legend

Data represent number (%) of patients with all cause adverse events by worst grade, occurring between the first dose and 90 days after the last dose of study therapy. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

Abbreviation: NC/NA, no change from baseline/no adverse event.

All Cause Serious Adverse Events (10 mg/kg)

Name	Grade	Attribution
Malignant neoplasm progression	5	Unrelated
Malignant neoplasm progression	5	Unrelated
Dysphagia	3	Unrelated
Lung infection	2	Unrelated
Pneumonia	2	Unrelated
Sensorimotor disorder	3	Unrelated

Serious Adverse Events Legend

Data represent number (%) of patients with all serious cause adverse events by worst grade, occurring between the first dose and 90 days after the last dose of study therapy. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

See also Tables 5, 6, and 7 for detailed summaries of all related AEs, all cause adverse events, and all cause SAEs.

Table 5.

All related adverse events

Adverse event	Grade, n (%)					Total, n (%)
	1	2	3	4	5
Ipilimumab 3 mg/kg (n = 11)
Pruritus	3 (27.3)	2 (18.2)	0	0	0	5 (45.5)
Rash	3 (27.3)	2 (18.2)	0	0	0	5 (45.5)
Aspartate aminotransferase increased	3 (27.3)	1 (9.1)	0	0	0	4 (36.4)
Nausea	3 (27.3)	0	0	0	0	3 (27.3)
Asthenia	2 (18.2)	0	0	0	0	2 (18.2)
Pain	1 (9.1)	1 (9.1)	0	0	0	2 (18.2)
Pyrexia	2 (18.2)	0	0	0	0	2 (18.2)
Vomiting	2 (18.2)	0	0	0	0	2 (18.2)
Alanine aminotransferase increased	0	1 (9.1)	0	0	0	1 (9.1)
Chest discomfort	1 (9.1)	0	0	0	0	1 (9.1)
Dizziness	1 (9.1)	0	0	0	0	1 (9.1)
Dreamy state	1 (9.1)	0	0	0	0	1 (9.1)
Emotional disorder	0	1 (9.1)	0	0	0	1 (9.1)
Fatigue	1 (9.1)	0	0	0	0	1 (9.1)
Flushing	1 (9.1)	0	0	0	0	1 (9.1)
Gastrointestinal disorder	1 (9.1)	0	0	0	0	1 (9.1)
Hyperthyroidism	1 (9.1)	0	0	0	0	1 (9.1)
Hypothyroidism	0	1 (9.1)	0	0	0	1 (9.1)
Mouth ulceration	1 (9.1)	0	0	0	0	1 (9.1)
Pigmentation disorder	0	1 (9.1)	0	0	0	1 (9.1)
Pruritus generalized	1 (9.1)	0	0	0	0	1 (9.1)
Skin exfoliation	0	1 (9.1)	0	0	0	1 (9.1)
Somnolence	1 (9.1)	0	0	0	0	1 (9.1)
Thyroid disorder	1 (9.1)	0	0	0	0	1 (9.1)
Ipilimumab 10 mg/kg (n = 14)
Fatigue	4 (28.6)	2 (14.3)	0	0	0	6 (42.9)
Hypothyroidism	3 (21.4)	1 (7.1)	0	0	0	4 (28.6)
Blister	1 (7.1)	0	0	0	0	1 (7.1)
Erythema	0	0	1 (7.1)	0	0	1 (7.1)
Granulocytosis	1 (7.1)	0	0	0	0	1 (7.1)
Hyperthyroidism	1 (7.1)	0	0	0	0	1 (7.1)
Hyponatremia	1 (7.1)	0	0	0	0	1 (7.1)
Leukocytosis	1 (7.1)	0	0	0	0	1 (7.1)
Pharyngitis	1 (7.1)	0	0	0	0	1 (7.1)
Productive cough	1 (7.1)	0	0	0	0	1 (7.1)
Pruritus	1 (7.1)	0	0	0	0	1 (7.1)
Pyrexia	0	1 (7.1)	0	0	0	1 (7.1)
Rash	0	1 (7.1)	0	0	0	1 (7.1)
Vomiting	1 (7.1)	0	0	0	0	1 (7.1)

Data represent number (%) of patients with all cause adverse events by worst grade, occurring between the first dose and 90 days after the last dose, of study therapy. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

Table 6.

All cause adverse events

Adverse event	Grade, n (%)					Total, n (%)
	1	2	3	4	5
Ipilimumab 3 mg/kg (n = 11)
Pruritus	3 (27.3)	2 (18.2)	0	0	0	5 (45.5)
Rash	3 (27.3)	2 (18.2)	0	0	0	5 (45.5)
Aspartate aminotransferase increased	3 (27.3)	1 (9.1)	0	0	0	4 (36.4)
Constipation	1 (9.1)	3 (27.3)	0	0	0	4 (36.4)
Cough	3 (27.3)	1 (9.1)	0	0	0	4 (36.4)
Malignant neoplasm progression	0	0	0	0	4 (36.4)	4 (36.4)
Weight decreased	2 (18.2)	2 (18.2)	0	0	0	4 (36.4)
Anemia	0	3 (27.3)	0	0	0	3 (27.3)
Decreased appetite	2 (18.2)	1 (9.1)	0	0	0	3 (27.3)
Nausea	3 (27.3)	0	0	0	0	3 (27.3)
Asthenia	2 (18.2)	0	0	0	0	2 (18.2)
Blood lactate dehydrogenase	0	2 (18.2)	0	0	0	2 (18.2)
Dizziness	2 (18.2)	0	0	0	0	2 (18.2)
Hypokalemia	0	0	2 (18.2)	0	0	2 (18.2)
Hyponatremia	0	0	1 (9.1)	1 (9.1)	0	2 (18.2)
Hypoproteinemia	1 (9.1)	1 (9.1)	0	0	0	2 (18.2)
Pain	1 (9.1)	1 (9.1)	0	0	0	2 (18.2)
Pyrexia	2 (18.2)	0	0	0	0	2 (18.2)
Vomiting	1 (9.1)	1 (9.1)	0	0	0	2 (18.2)
Abdominal pain	0	1 (9.1)	0	0	0	1 (9.1)
Alanine aminotransferase increased	0	1 (9.1)	0	0	0	1 (9.1)
Blood alkaline phosphatase increased	1 (9.1)	0	0	0	0	1 (9.1)
Blood creatinine increased	1 (9.1)	0	0	0	0	1 (9.1)
Chest discomfort	1 (9.1)	0	0	0	0	1 (9.1)
Chest pain	0	1 (9.1)	0	0	0	1 (9.1)
Dreamy state	1 (9.1)	0	0	0	0	1 (9.1)
Electrocardiogram QT prolonged	1 (9.1)	0	0	0	0	1 (9.1)
Emotional disorder	0	1 (9.1)	0	0	0	1 (9.1)
Fatigue	1 (9.1)	0	0	0	0	1 (9.1)
Flushing	1 (9.1)	0	0	0	0	1 (9.1)
Gamma‐glutamyltransferase increased	0	1 (9.1)	0	0	0	1 (9.1)
Gastrointestinal disorder	1 (9.1)	0	0	0	0	1 (9.1)
Hyperkalemia	0	1 (9.1)	0	0	0	1 (9.1)
Hyperthyroidism	1 (9.1)	0	0	0	0	1 (9.1)
Hypothyroidism	0	1 (9.1)	0	0	0	1 (9.1)
Insomnia	0	1 (9.1)	0	0	0	1 (9.1)
Mouth ulceration	1 (9.1)	0	0	0	0	1 (9.1)
Neurotoxicity	1 (9.1)	0	0	0	0	1 (9.1)
Otitis media	1 (9.1)	0	0	0	0	1 (9.1)
Pain in extremity	0	1 (9.1)	0	0	0	1 (9.1)
Pigmentation disorder	0	1 (9.1)	0	0	0	1 (9.1)
Platelet count increased	1 (9.1)	0	0	0	0	1 (9.1)
Pneumonia	0	1 (9.1)	0	0	0	1 (9.1)
Productive cough	1 (9.1)	0	0	0	0	1 (9.1)
Pruritus generalized	1 (9.1)	0	0	0	0	1 (9.1)
Skin disorder	0	1 (9.1)	0	0	0	1 (9.1)
Skin exfoliation	0	1 (9.1)	0	0	0	1 (9.1)
Somnolence	1 (9.1)	0	0	0	0	1 (9.1)
Tachypnoea	0	1 (9.1)	0	0	0	1 (9.1)
Thyroid disorder	1 (9.1)	0	0	0	0	1 (9.1)
Urine abnormality	0	1 (9.1)	0	0	0	1 (9.1)
Ipilimumab 10 mg/kg (n = 14)
Fatigue	4 (28.6)	2 (14.3)	0	0	0	6 (42.9)
Hypothyroidism	2 (14.3)	2 (14.3)	0	0	0	4 (28.6)
Anemia	2 (14.3)	1 (7.1)	0	0	0	3 (21.4)
Aspartate aminotransferase increased	2 (14.3)	0	1 (7.1)	0	0	3 (21.4)
Constipation	3 (21.4)	0	0	0	0	3 (21.4)
Hyponatremia	1 (7.1)	0	2 (14.3)	0	0	3 (21.4)
Weight decreased	2 (14.3)	1 (7.1)	0	0	0	3 (21.4)
Alanine aminotransferase increased	2 (14.3)	0	0	0	0	2 (14.3)
Back pain	0	2 (14.3)	0	0	0	2 (14.3)
Blood albumin decreased	1 (7.1)	1 (7.1)	0	0	0	2 (14.3)
Blood blister	2 (14.3)	0	0	0	0	2 (14.3)
C‐reactive protein increased	2 (14.3)	0	0	0	0	2 (14.3)
Hemangioma	2 (14.3)	0	0	0	0	2 (14.3)
Leukocytosis	1 (7.1)	1 (7.1)	0	0	0	2 (14.3)
Malignant neoplasm progression	0	0	0	0	2 (14.3)	2 (14.3)
Neutrophil count increased	1 (7.1)	1 (7.1)	0	0	0	2 (14.3)
Productive cough	1 (7.1)	1 (7.1)	0	0	0	2 (14.3)
Pruritus	2 (14.3)	0	0	0	0	2 (14.3)
Pyrexia	1 (7.1)	1 (7.1)	0	0	0	2 (14.3)
Rash	1 (7.1)	1 (7.1)	0	0	0	2 (14.3)
Vomiting	1 (7.1)	1 (7.1)	0	0	0	2 (14.3)
Arthralgia	1 (7.1)	0	0	0	0	1 (7.1)
Blister	1 (7.1)	0	0	0	0	1 (7.1)
Blood glucose increased	1 (7.1)	0	0	0	0	1 (7.1)
Blood lactate dehydrogenase increased	0	1 (7.1)	0	0	0	1 (7.1)
Capillary disorder	1 (7.1)	0	0	0	0	1 (7.1)
Chest pain	0	1 (7.1)	0	0	0	1 (7.1)
Decreased appetite	0	1 (7.1)	0	0	0	1 (7.1)
Dysphagia	0	0	1 (7.1)	0	0	1 (7.1)
Dyspnea exertional	0	1 (7.1)	0	0	0	1 (7.1)
Edema peripheral	1 (7.1)	0	0	0	0	1 (7.1)
Epistaxis	1 (7.1)	0	0	0	0	1 (7.1)
Erythema	0	0	1 (7.1)	0	0	1 (7.1)
Gingival bleeding	1 (7.1)	0	0	0	0	1 (7.1)
Granulocytosis	1 (7.1)	0	0	0	0	1 (7.1)
Hypercholesterolemia	1 (7.1)	0	0	0	0	1 (7.1)
Hyperthyroidism	1 (7.1)	0	0	0	0	1 (7.1)
Hyperuricemia	1 (7.1)	0	0	0	0	1 (7.1)
Hypoesthesia	0	0	1 (7.1)	0	0	1 (7.1)
Hypoalbuminemia	1 (7.1)	0	0	0	0	1 (7.1)
Increased viscosity of upper respiratory secretion	0	1 (7.1)	0	0	0	1 (7.1)
Lung infection	0	1 (7.1)	0	0	0	1 (7.1)
Lymphadenopathy	0	1 (7.1)	0	0	0	1 (7.1)
Muscle fatigue	1 (7.1)	0	0	0	0	1 (7.1)
Nausea	0	1 (7.1)	0	0	0	1 (7.1)
Otitis media	0	1 (7.1)	0	0	0	1 (7.1)
Pain	0	1 (7.1)	0	0	0	1 (7.1)
Paronychia	0	1 (7.1)	0	0	0	1 (7.1)
Peripheral sensorimotor neuropathy	0	0	1 (7.1)	0	0	1 (7.1)
Peripheral swelling	1 (7.1)	0	0	0	0	1 (7.1)
Pharyngitis	1 (7.1)	0	0	0	0	1 (7.1)
Pneumonia	0	1 (7.1)	0	0	0	1 (7.1)
Pyelonephritis acute	1 (7.1)	0	0	0	0	1 (7.1)
Rhinorrhea	1 (7.1)	0	0	0	0	1 (7.1)
Sensorimotor disorder	0	0	1 (7.1)	0	0	1 (7.1)
Sinusitis	1 (7.1)	0	0	0	0	1 (7.1)
Stomatitis	1 (7.1)	0	0	0	0	1 (7.1)

Data represent number (%) of patients with all cause adverse events by worst grade, occurring between the first dose and 90 days after the last dose of study therapy. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

Table 7.

All cause serious adverse events

Adverse event	Grade, n (%)
	1	2	3	4	5
Ipilimumab 3 mg/kg (n = 11)
Malignant neoplasm progression	0	0	0	0	4 (36.4)
Chest pain	0	1 (9.1)	0	0	0
Hyponatremia	0	0	0	1 (9.1)	0
Ipilimumab 10 mg/kg (n = 14)
Malignant neoplasm progression	0	0	0	0	2 (14.3)
Dysphagia	0	0	1 (7.1)	0	0
Lung infection	0	1 (7.1)	0	0	0
Pneumonia	0	1 (7.1)	0	0	0
Sensorimotor disorder	0	0	1 (7.1)	0	0

Data represent number (%) of patients with all cause adverse events by worst grade, occurring between the first dose and 90 days after the last dose of study therapy. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

Pharmacokinetics/Pharmacodynamics

Dose level	Number enrolled	Cmax (μg/L) mean ± SD	AUC0–12 (h*12μg/L) mean ± SD
3 mg/kg	11	60 (15)	10,620 (32)
10 mg/kg	14	191 (13)	35,679 (22)

Abbreviations: AUC, area under the curve; C_max, maximum serum concentration.

Assessment, Analysis, and Discussion

Completion	Study completed
Investigator's Assessment	Drug tolerable, efficacy was not fully evaluable due to limited patient numbers, it warrants exploration in a larger study of patients with malignant melanoma and nasopharyngeal carcinoma.

Ipilimumab is a human monoclonal antibody that binds CTLA‐4, a negative regulator of T cells, preventing ligand interaction on antigen‐presenting cells [1]. Ipilimumab is approved for the treatment of advanced melanoma in >45 countries (3 mg/kg) and in the U.S. for unresectable or metastatic melanoma (10 mg/kg) [2]. Prognosis for patients with metastatic and refractory solid tumors is poor (median survival <10 months), and there is an unmet medical need to address this, in China and globally [3, 4].

The safety profile has been established in over 12,700 clinical study patients, with the most common adverse events (AEs) being medically manageable immune‐mediated events, consistent with the mechanism of action [6]. Existing knowledge of the safety, tolerability, and pharmacokinetics of ipilimumab is based on data from a predominantly White population [1, 5, 6].

This study (NCT02516527) assessed ipilimumab safety, tolerability, and pharmacokinetics (PK) in Chinese patients with advanced unresectable, metastatic, or recurrent malignant melanoma (MM), or nasopharyngeal carcinoma (NPC). Secondary objectives included assessing immunogenicity and preliminary antitumor activity.

The study was an open‐label, single‐center, phase 1b dose escalation study of ipilimumab in Chinese patients. There were three periods in the trial: screening (≤28 days), treatment (until disease progression or intolerable toxicity), and follow‐up (≥90 days). Within the induction phase of the treatment period, patients received 3 mg/kg ipilimumab every 3 weeks (i.v., day 1 of a 3‐week cycle, repeated up to four times or until progressive disease). The maintenance phase started at week 24 (i.v., day 1 of a 12‐week cycle), continuing to 3 years from first dose, dependent on disease. Patients received a last dose when there was disease progression, clinical deterioration, and the investigator assessed intolerability or unlikely further treatment benefit, or the study discontinuation criteria were met. Subsequently, patient follow‐up was initiated and continued for a minimum of 90 days. During follow‐up, AEs were categorized as resolved, returned to baseline, or considered irreversible. To assess the safety of ipilimumab, the successive ascending dose (10 mg/kg) was administered by a 9 + 9 design, taking into consideration the safety and PK co‐endpoints. Additional subjects were allowed to join during the enrollment phase, as this is a phase I open‐label study.

The study included Chinese adults (aged ≥18 years) with histologically or cytologically confirmed solid MM or NPC tumors that were advanced (unresectable, metastatic or recurrent), Eastern Cooperative Oncology Group performance status of 0 or 1, and with adequate organ function. Exclusion criteria included central nervous system metastases, prior malignancy (except for nonmelanoma or certain in situ cancers, or complete remission ≤2 years), autoimmune disease, active or latent tuberculosis infection, pregnancy, prior immunotherapy or immunosuppressive agent treatment, any anticancer therapy or radiation therapy within 4 weeks of study drug administration, use of traditional Chinese medicines within 2 weeks of study drug administration, and use of steroids at doses >10 mg/day.

PK samples were collected after the first dose to characterize ipilimumab exposure at baseline and at 1.5 (end of infusion), 4, 24, 48, 168, 336, and 504 hours after dose. After the first dose, the following were calculated: maximum serum concentration (C_max), time to achieve C_max (T_max), and area under the curve during the dosing interval of 504 hours (AUC_t). Additional trough samples were also collected at the predose timepoints and at weeks 7, 10, 24, and every 12 weeks thereafter, until discontinuation or a maximum of 3 years of study treatment.

Of the 39 patients enrolled, 25 patients received at least one dose of ipilimumab and were evaluable for safety (11 patients received the 3 mg/kg dose, and 14 patients received the 10 mg/kg dose; Table 1 and Fig. 2). The median patient age in the 3 mg/kg group was 44 years (range: 23–68 years) and 48 years (range: 23–57 years) in the 10 mg/kg group (Table 2). In both groups the majority (71–73%) were male (Table 2). In the 3 mg/kg treatment group, six patients were being treated for MM and five for NPC (Table 2). In the 10 mg/kg group all 14 patients were treated for NPC (Table 2). Most (84%) patients had received at least two prior lines of systemic anticancer therapy (Table 2). During the study all patients discontinued treatment, mostly due to disease progression (23 patients, 92%; Table 2). There was one event of drug‐related toxicity leading to discontinuation and one death (Table 2).

Table 1.

Summary of safety data

Death or adverse event	3 mg/kg treatment group (n = 11)			10 mg/kg treatment group (n = 14)
	All grades (1–5)	Grade 3–4 a	Grade 5	All grades (1–5)	Grade 3–4 a	Grade 5
Death	4 (36.4)			3 (21.4)
Disease‐related death	4 (36.4)			3 (21.4)
Drug‐related toxicity	0			0
SAEs
All causality	5 (45.5)	0	4 (36.4)	5 (35.7)	2 (14.3)	2 (14.3)
Drug‐related	0	0	0	0	0	0
SOC: Neoplasms benign, malignant, and unspecified	4 (36.4)	0	4 (36.4)	2 (14.3)	0	2 (14.3)
PT: Malignant neoplasm progression	4 (36.4)	0	4 (36.4)	2 (14.3)	0	2 (14.3)
SOC: General disorders and administration site conditions	1 (9.1)	0	0	0	0	0
PT: Chest pain	1 (9.1)	0	0	0	0	0
SOC: Metabolism and nutrition disorders	1 (9.1)	1 (9.1)	0	0	0	0
PT: Hyponatremia	1 (9.1)	1 (9.1)	0	0	0	0
SOC: Gastrointestinal disorders	0	0	0	1 (7.1)	1 (7.1)	0
PT: Dysphagia	0	0	0	1 (7.1)	1 (7.1)	0
SOC: Infections and infestations	0	0	0	1 (7.1)	0	0
PT: Lung infections	0	0	0	1 (7.1)	0	0
PT: Pneumonia	0	0	0	1 (7.1)	0	0
SOC: Nervous system disorders	0	0	0	1 (7.1)	1 (7.1)	0
PT: Sensorimotor disorder	0	0	0	1 (7.1)	1 (7.1)	0
AEs
All causality	11 (100.0)	0	0	14 (100.0)	4 (28.6)	0
Drug‐related (ADR)	11 (100.0)	0	0	11 (78.6)	1 (7.1)	0
Leading to discontinuation (all causality)	2 (18.2)	0	0	2 (14.3)	1 (7.1)	0
Drug‐related (ADR)	1 (9.1)	0	0	0	0	0
SOC: Endocrine disorders	1 (9.1)	0	0	0	0	0
PT: Hypothyroidism	1 (9.1)	0	0	0	0	0
AEs by PT b
Pruritus	5 (45.5)	0	0	2 (14.3)	0	0
Rash	5 (45.5)	0	0	2 (14.3)	0	0
AST increased	4 (36.4)	0	0	3 (21.4)	1 (7.1)	0
Constipation	4 (36.4)	0	0	3 (21.4)	0	0
Cough	4 (36.4)	0	0	2 (14.3)	0	0
Malignant neoplasm progression	4 (36.4)	0	0	2 (14.3)	0	0
Weight decreased	4 (36.4)	0	0	3 (21 .4)	0	0
Anemia	3 (27.3)	0	0	3 (21 .4)	0	0
Appetite decreased	3 (27.3)	0	0	1 (7.1)	0	0
Nausea	3 (27.3)	0	0	1 (7.1)	0	0
Fatigue	1 (9.1)	0	0	6 (42.9)	0	0
Hypothyroidism	1 (9.1)	0	0	4 (28.6)	0	0

^aMost severe grade of events recorded.

^bReported for ≥25% patients, in either group or of any grade.

Abbreviations: ADR, adverse drug reaction; AE, adverse event; AST, aspartate aminotransferase; PT, preferred term; SAE, serious adverse event; SOC, system organ class.

Figure 2.

Patient disposition. ^aThe percentage refers to the proportion of patients entering the maintenance phase. ^bThe percentage refers to the proportion of patients treated in the dose group.

The median (range) of cumulative doses was 11.9 mg/kg (9.0–12.3) in patients with MM treated with 3 mg/kg ipilimumab, 11.7 mg/kg (3.0–15.3) in patients with NPC treated with 3 mg/kg ipilimumab, and 35.1 mg/kg (10.0–58.8) in patients with NPC treated with 10 mg/kg ipilimumab. The median duration (range) of treatment was 12.1 weeks (8.3–12.7) in patients with MM treated with 3 mg/kg ipilimumab, 12.0 weeks (3.0–32.1) in patients with NPC treated with 3 mg/kg ipilimumab, and 10.5 weeks (3.0–38.0) in patients with NPC treated with 10 mg/kg ipilimumab.

Safety profiles and cross‐dose comparisons observed in Chinese patients and prior U.S. clinical data (NCT00729950 and NCT00920907) were similar. There were no new safety signals, drug‐related deaths, or drug‐related serious adverse events. Most AEs affected the skin (14/25 patients), liver (7/25), endocrine system (6/25), or gastrointestinal tract (5/25) and were grades 1–2. There were 11 patients in each dose group with adverse drug reactions (ADRs), also most affecting skin, liver, endocrine system, and gastrointestinal tract, one ADR of hypothyroidism led to discontinuation (3 mg/kg), and there were no discontinuations from the 10 mg/kg group. Ipilimumab was tolerated, with only one dose‐limiting toxicity (erythema; 10 mg/kg treated patient with NPC). There were no hypersensitivity or infusion reactions.

First dose AUC_t and C_max increased dose‐proportionally (Fig. 1A). Ipilimumab exposure (assessed by AUC_t and C_max) was lower for both doses in Chinese than in U.S. patients. The serum concentration in these populations overlapped, suggesting that ipilimumab PK was ethnically insensitive in the populations compared (Fig. 1B and C). Monoclonal antibodies, such as ipilimumab, are cleared from the body by nonspecific mechanisms that do not show genetic polymorphic, ethnically influenced inhibition or induction [7, 8, 9]. During the induction phase, steady state was reached by approximately week 10 for both the 3 mg/kg and 10 mg/kg groups, based on trough concentrations (Fig. 3).

Figure 3.

Geometric mean ipilimumab trough. (A): 3 mg/kg. (B): 10 mg/kg. Bars indicate 95% confidence intervals.

Immunogenicity was assessed by formation of antidrug antibodies (ADAs). In the 3 mg/kg group 10 of 11 patients (91%) and in the 10 mg/kg group 13 of 14 (93%) of patients were evaluable for ADAs, with baseline and at least one postbaseline ADA assessment (Table 3). No immunogenicity events affected the safety profile.

Table 3.

Ipilimumab treatment immunogenicity

ADA status	Ipilimumab 3 mg/kg (n = 10), n (%)	Ipilimumab 10 mg/kg (n = 13), n (%)
ADA positive a	1 (10)	2 (15.4)
PP b	0	0
Not PP–last sample positive c	1 (10)	0
Other positive d	0	2 (15.4)
ADA negative	9 (90)	11 (84.6)

^aAt least one ADA positive (ADA+) sample relative to baseline after treatment initiation.

^bADA+ samples at at least two consecutive timepoints.

^cNot PP, but ADA+ during the last sampling.

^dNot PP, some ADA+, with the last sampling being negative. Data shown are for patients with baseline ADA data and at least one postbaseline ADA assessment.

Abbreviations: ADA, antidrug antibody; PP, persistent positive.

Preliminary antitumor activity was assessed for all patients. The investigators assessed best overall response using RECIST version 1.1 criteria [10]. Of the six patients with MM (3 mg/kg), five patients had progressive disease (PD) and one was not evaluable (NE), and three of the five patients with NPC had PD, one was NE, and one had stable disease (SD). In the 10 mg/kg group (n = 14 patients with NPC), 11 had PD, 2 had SD, and 1 was NE. The disease control rates (DCRs) were 20% (a confidence interval was not applicable, as ≤10 patients) and 14.3% (95% confidence interval [CI]: 1.8–42.8) for the 3 mg/kg and 10 mg/kg ipilimumab treated patients with NPC, respectively (Table 4). The DCR was zero in the six patients with MM (Table 4), which was likely due to the advanced stage of disease at enrollment (Table 1) and the small sample size. For further exploration of the efficacy of ipilimumab in patients with MM or NPC, further studies with larger cohorts are warranted.

Table 4.

Antitumor responses

Response	Ipilimumab 3 mg/kg		Ipilimumab 10 mg/kg		Total
	MM (n = 6)	NPC (n = 5)	MM (n = 0)	NPC (n = 14)	MM (n = 6)	NPC (n = 14)
Best overall response, n (%)
CR	0	0	0	0	0	0
PR	0	0	0	0	0	0
SD	0	1 (20)	0	2 (14)	0	3 (16)
PD	5 (83)	3 (60)	0	11 (79)	5 (83)	14 (74)
NE	1 (17)	1 (20)	0	1 (7)	1 (17)	2 (11)
ORR a , n (% [95% CI]) b	0	0	0	0	0
DCR c , n (% [95% CI]) b	0	1 (20)	0	2 (14 [2–43])	0	3 (16 [3–40])

^aThe proportion of patients whose best overall response is either a CR or a PR.

^bConfidence intervals were computed for cohorts of 10 patients or more only.

^cThe proportion of patients with a CR or PR or who achieved SD.

Abbreviations: CI, confidence interval; CR, complete response; DCR, disease control rate; MM, malignant melanoma; NE, not evaluable; NPC, nasopharyngeal carcinoma; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

The median (range) follow‐up duration for patients treated with 3 mg/kg and 10 mg/kg ipilimumab was 4.9 (1.3–14.1) months and 4.8 (0.9–11.2) months, respectively. The median progression‐free survival (PFS) Kaplan‐Meier estimate was 10.1 (95% CI: 3.9–11.1) weeks in the patients with NPC treated with 10 mg/kg ipilimumab, and median overall survival Kaplan‐Meier estimate was not reached. For patients treated with 10 mg/kg ipilimumab, the PFS rate estimate at 24 weeks was 14.3% (95% CI: 2.3–36.6), and the overall survival rate estimate at 24 weeks was 76.6% (95% CI: 43.3–91.9).

Ipilimumab was well tolerated in Chinese patients, showing similar safety and pharmacokinetic profiles to previous studies in predominantly White patients. There were no new safety signals, hypersensitivity, or infusion reactions. In these pretreated patients with advanced or recurrent NPC, preliminary antitumor responses are considered worthy of further study in a larger patient population.

Disclosures

Sai Praneeth Bathena: Bristol‐Myers Squibb (E); Amol Tendolkar: Bristol‐Myers Squibb (E, OI); Jennifer Sheng: Bristol‐Myers Squibb (E, OI); Li Zhang: Bristol‐Myers Squibb, Roche, Pfizer, CTTQ Pharma, Hengrui Medicine, Innovent Bio (RF). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board