Phase 1, Open-Label, Dose Escalation Study of Anti-CD98 Monoclonal Antibody KHK2898 as Monotherapy in Subjects With Advanced Solid Tumors Who No Longer Respond to Standard Therapy or For Whom No Standard Therapy Is Available
1. The subject has a histopathological-documented, measurable or non-measurable, locally
advanced unresectable primary or metastatic solid tumor unresponsive to standard
therapy or for which there is no standard therapy available.
2. The subject has PD during or following the last treatment regimen as defined by the
Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v 1.1 guidelines)11.
3. The subject has a life expectancy >3 months.
4. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status (PS)
score of ≤ 2 at study entry.
5. The subject is ≥ 18 years of age.
6. The subject has a pre-study echocardiogram or multigated acquisition scan with left
ventricular ejection fraction ≥ 50%.
7. The subject has recovered to Grade ≤ 1 by the CTCAE v 4.0313, from the effects of
recent surgery, radiotherapy, chemotherapy, hormonal therapy, or other targeted
therapies for cancer, with the exception of alopecia or peripheral neuropathy (the
latter of which must have resolved to Grade ≤ 2).
8. The subject has preserved organ function as defined below. All parameters must be
evaluated within 7 days prior to the first dose of KHK2898.
- 8-a) Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 ×Upper limits
of normal (ULN), or ≤ 5.0 × ULN in subjects with metastatic liver disease
- 8-b) Hemoglobin ≥ 9 g/dl (without transfusion in the preceding 7 days)
- 8-c) Total bilirubin ≤ 1.5 × ULN
- 8-d) Creatinine ≤ 1.5 × ULN
- 8-e) ANC ≥ 1.5 × 109/L (unsupported by growth factors in the preceding 21 days)
- 8-f) Platelets ≥ 100 × 109/L (without transfusion or growth factor in the
preceding 7 days)
9. The subject has provided signed informed consent. Written informed consent must be
obtained prior to performing any study-related procedures. For subject < 21 years old
who is not married, written informed consent must be taken from the subject and
his/her parents/ legal guardians.
10. Women of childbearing potential (WOCBP) must have a negative pregnancy test at study
entry. Subjects not considered WOCBP are those without menses for 24 consecutive
months, and those who have undergone hysterectomy and/or bilateral
salpingo-oophorectomy. WOCBP must be willing to use acceptable methods of birth
control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with
spermicide, or condom with spermicide, or abstinence) for the duration of the study.
1. The subject has received anti-cancer chemotherapy, hormonal therapy (other than LH-RH
agonists/pure antagonists for prostate cancer, which are allowed to be continued if
the subject has already been on one for at least 2 months at the time of enrollment),
radiotherapy, immunotherapy, or investigational agents within 4 weeks (6 weeks for
mitomycin C and nitrosoureas) prior to the first dose of KHK2898.
2. The subject has received monoclonal antibodies within 4 weeks of the first dose of
3. The subject had major surgery within 4 weeks prior to the first dose of KHK2898.
4. The subject has known symptomatic brain metastases (screening/baseline MRI of the
brain is only required when there is clinical suspicion of central nervous system
(CNS) involvement or past history of treated brain metastasis). Subjects with treated
brain metastasis (radiotherapy and/or surgery) will be eligible if:
- 4-a) They have completed treatment for their brain metastasis > 4 weeks prior
to scheduled study treatment start date;
- 4-b) They are neurologically stable;
- 4-c) They are not receiving corticosteroids or corticosteroids in doses no
greater than physiological replacement (e.g., dexamethasone < 1.5 mg/day); and
- 4-d) They have a screening/baseline MRI scan of the brain that specifically
verifies no evidence of CNS hemorrhage and no active gadolinium enhancing
- 4-e) Subjects with primary brain/CNS malignancy (e.g., gliomas, lymphomas)
5. The subject has leptomeningeal disease.
6. The subject is pregnant (confirmed by beta human chorionic gonadotrophin [β-HCG]) or
7. The subject has a significant uncontrolled intercurrent illness including, but not
limited to: ongoing or active infection requiring parenteral antibiotics, clinically
significant cardiac disease [class II, III, or IV of the New York Heart Association
classification (NYHA)],14 unstable angina pectoris, myocardial infarction within 6
months or is post angioplasty or stenting within 6 months, uncontrolled hypertension
(i.e., systolic blood pressure (BP) > 150 mm Hg, diastolic BP > 90 mm Hg), found on
two consecutive measurements separated by a 1-week period, clinically significant
cardiac arrhythmia, or uncontrolled diabetes.
8. The subject has known human immunodeficiency virus infection or acquired
immunodeficiency syndrome-related illness.
9. The subject has known active hepatitis B or C or other active (non-malignant) liver
10. The subject has a psychiatric illness, disability or social situation that would
compromise the subject's safety, ability to provide consent, or limit his/her
compliance with study requirements.
11. The subject has experienced a hypersensitivity reaction to monoclonal antibodies or
other therapeutic proteins, and the reaction could not be controlled or prevented on
subsequent infusion with standard therapies such as antihistamines, 5-HT3
antagonists, or corticosteroids.
12. The subject has a history of another primary cancer, with the exception of: a)
curatively resected nonmelanomatous skin cancer, b) curatively treated cervical
carcinoma in-situ, or c) other primary solid tumor treated with curative intent and
no known active disease present and no treatment administered during the last 3
13. The subject requires concomitant medication with any of the following prohibited
medications: active prohibited anti neoplastic treatment other than the
investigational product KHK2898; other anti-cancer therapies such as cytotoxic
chemotherapy; anti-cancer hormonal therapy other than LH-RH agonists/pure antagonists
for prostate cancer, which are allowed to be continued if the subject has already
been on one for at least 2 months at the time of enrollment; immunotherapies
including other monoclonal antibodies, interferons, cancer vaccines, etc; targeted
small molecule anti-cancer therapies; and radiation therapy (radiation therapy should
be completed prior to enrollment on this study).
14. Prior stem cell or bone marrow transplant.
15. Subjects received vaccination within 8 weeks from the first administration of