Study of Anti-HB-EGF Antibody KHK2866 in Subjects With Advanced Solid Tumors and Ovarian Cancer

Phase 1 Study of Anti-HB-EGF Monoclonal Antibody KHK2866 as Monotherapy in Subjects With Advanced Solid Tumors and in Combination With Chemotherapy in Ovarian Cancer

This is a two-part, Phase 1, open-label, multicenter, dose escalation study of KHK2866 as monotherapy in patients with advanced solid tumors, and in combination with chemotherapy in subjects platinum-sensitive and platinum-resistant ovarian cancer.

Study Overview

• Status: Terminated
• Conditions: Neoplasms; Ovarian Neoplasms; Fallopian Tube Neoplasms; Primary Peritoneal Neoplasm
• Intervention / Treatment: Biological: KHK2866; Drug: Gemcitabine and Carboplatin; Drug: paclitaxel; Drug: pegylated liposomal doxorubicin

Detailed Description

During Phase 1a, groups of eligible patients with advanced solid tumors will receive KHK2866 as monotherapy in escalating doses. The Phase 1b portion will enroll patients with ovarian cancer who will receive KHK2866 in combination with one of three chemotherapy regimens (Arms): gemcitabine+carboplatin (platinum-sensitive, weekly paclitaxel (platinum-resistant), or pegylated liposomal doxorubicin (platinum-resistant). Escalating doses of the combination of KHK2866 and the chemotherapy regimen will given to two groups of subjects per Arm. The goal of the study is to learn about the side effects of KHK2866 alone or given in combination with chemotherapy. All subjects will receive study therapy for up to 6 cycles (up to 12 cycles for subjects assigned to PLD [Arm 3 of Phase 1b]), or until disease progression, the development of severe side effects, noncompliance or withdrawal of consent by the subject, or other removal criteria whichever comes first.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Arizona Cancer Center
  • California
    • Los Angeles, California, United States, 90033
      • USC Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90048
      • Cedar Sinai-Samuel Oschin Comprehensive Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Texas
    • Houston, Texas, United States, 77030
      • Oncology Consultants
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy and Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically documented, measurable or non-measurable, advanced primary or recurrent solid tumor (Phase 1a only) which is unresponsive to standard therapy or for which there is no standard therapy available.
• Histologically or cytologically documented ovarian, primary peritoneal, or fallopian tube cancer.
• The subject has objective radiographic disease progression and either unmeasurable or measurable disease during or following the last treatment regimen, or serum cancer antigen-125 (CA-125) greater than 2X the upper limit of normal ([ULN] >70 U/mL
• Life expectancy >3 months.
• Performance status < 3 at study entry.
• Age > 18 years.
• Normal left ventricular ejection fraction.
• Recovered from the effects of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or other therapies for cancer
• Preserved hepatic, renal, and hematopoetic organ function.
• Male and female subjects must use medically accepted contraception.

Exclusion Criteria:

• Ovarian malignancy of low malignant potential.
• Received anti-cancer chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or investigational agents within 4 weeks prior to the first dose of KHK2866 (6 weeks for nitrosourea or mitomycin chemotherapy).
• received Mabs or had major surgery within 4 weeks of the first dose of KHK2866.
• Requires administration of a prohibited medication or treatment including: prophylactic use of erythroid and/or granulocyte colony stimulating factors; concurrent anti-cancer treatment; biologic response modifiers for any condition
• Brain metastases, leptomeningeal or primary brain neoplasm, even if treated.
• Previously untreated or uncontrolled epidural metastasis
• Cerebrovascular accident, Transient ischemic attack; symptomatic head trauma, or seizures or any kind within 6 months
• Dementia, or other disorders of mentation or difficulty speaking or difficulty with comprehension.
• Suspected impending bowel obstruction
• The subject is pregnant,or is lactating.
• Significant uncontrolled intercurrent illness
• Known HIV infection or AIDS-related illness.
• Known active hepatitis B or C or other active liver disease.
• 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.
• Experienced a unmanageable hypersensitivity reactions to Mabs or other therapeutic proteins.
• History of second primary cancer, with the exception of: a) curatively resected non-melanomatous 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 2 years.

• Additional exclusion criteria for subjects proposed for enrollment into the Phase 1b portion:

  • History of hypersensitivity or infusion reaction to any of the proposed chemotherapy arm's agents that could not be controlled with pre-medication and/or infusion rate adjustment;
  • Prior treatment with KHK2866;
  • History of Grade ≥ 3 non-hematologic or Grade 4 hematologic toxicity attributable to any of the proposed chemotherapy arm's agents
  • For subjects proposed to receive treatment with KHK2866 plus PLD: prior total cumulative exposure to doxorubicin must be ≤ 240 mg/m2.
• Subjects with a known history of interstitial lung disease or pulmonary fibrosis. Subjects must have pulse oximetry >88% on room air at rest, and a DLco of >49% if there is no evidence of lung metastasis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: KHK2866 as monotherapy; Groups of subjects will receive a weekly infusions of KHK2866 as treatment for advanced cancer. If there no severe side effects, the dose will be increased for future subjects. A total of four groups are anticipated. Once an acceptable dose is determined an additional seven subjects will be treated at that dose.	Biological: KHK2866; Potentially therapeutic monoclonal antibody for the treatment of advanced cancer and ovarian cancer.
Experimental: KHK2866, gemcitabine+carboplatin; Open to subjects with ovarian, fallopian tube, or primary peritoneal cancer only. One group of subjects will receive one dose below the maximum tolerated dose of KHK2866 identified in Phase 1a along with gemcitabine and carboplatin. The dose of KHK2866 will be increased to the MTD for the next group if no severe side effects are noted. Once an acceptable dose is determined an additional seven subjects will be treated at that dose.	Biological: KHK2866; Potentially therapeutic monoclonal antibody for the treatment of advanced cancer and ovarian cancer.; Drug: Gemcitabine and Carboplatin; Combination chemotherapy with KHK2866 to treat advanced platinum-sensitive ovarian cancer. Gemcitabine dose 1000 mg/m2, Carboplatin dose AUC=4; Other Names: Gemzar, Paraplatin
Experimental: KHK2866, weekly paclitaxel; Open to subjects with ovarian, fallopian tube, or primary peritoneal cancer only. One group of subjects will receive one dose below the maximum tolerated dose of KHK2866 identified in Phase 1a along with weekly paclitaxel (80 mg/m2). The dose of KHK2866 will be increased to the MTD for the next group if no severe side effects are noted. Once an acceptable dose is determined an additional seven subjects will be treated at that dose.	Biological: KHK2866; Potentially therapeutic monoclonal antibody for the treatment of advanced cancer and ovarian cancer.; Drug: paclitaxel; Combination chemotherapy with KHK2866 to treat advanced platinum-resistant ovarian cancer. Paclitaxel will be administered weekly at a dose of 80 mg/m2.; Other Names: Taxol
Experimental: KHK2866, pegylated liposomal doxorubicin; Open to subjects with ovarian, fallopian tube, or primary peritoneal cancer only. One group of subjects will receive one dose below the maximum tolerated dose of KHK2866 identified in Phase 1a along with monthly PLD (40 mg/m2). The dose of KHK2866 will be increased to the MTD for the next group if no severe side effects are noted. Once an acceptable dose is determined an additional seven subjects will be treated at that dose.	Biological: KHK2866; Potentially therapeutic monoclonal antibody for the treatment of advanced cancer and ovarian cancer.; Drug: pegylated liposomal doxorubicin; Combination chemotherapy with KHK2866 to treat advanced platinum-resistant ovarian cancer. PLD will be administered weekly at a dose of 40 mg/m2.; Other Names: Doxil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Adverse Events as a Measure of Safety and Tolerability	The safety of KHK2866 will be determined by reported adverse events (AEs), changes in physical examinations, vital sign measurements, electrocardiograms (ECGs), clinical laboratory evaluations, and treatment discontinuation due to toxicity.	at least 60 days, and up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the Cmax, Tmax, AUC and half life of KHK2866 when administered i.v. as monotherapy	Participants will have serial blood samples taken to determine the PK profile of the study drug.	at least 28 days and up to 6 months
To evaluate the changes in serum HB-EGf in participants administered KHK2866	Participants will have serial blood samples taken to develop the PD profile.	at least 60 days, and up to 6 months
To screen for the development of antibodies against KHK2866 (immunogenicity).	Participants will have serial blood samples to check for the development of anti-KHK2866 antibodies.	at least 60 days and up to 6 months
To describe any anti-tumor activity observed when KHK2866 is administered i.v. as monotherapy, or in combination with chemotherapy.		at least 60 days and up to 6 months

Collaborators and Investigators

• Sponsor: Kyowa Hakko Kirin Pharma, Inc.
• Investigators: Study Director: Bruce A Silver, M.D., Kyowa Hakko Kirin Pharma, Inc.

Publications and helpful links

General Publications

• Sarantopoulos J, Mita MM, Birrer MJ, Cranmer LD, Campos LT, Zhang X, Bristow P, Kaito H, Strout V, Camacho LH. Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody, in Patients with Advanced Cancer. Target Oncol. 2016 Jun;11(3):317-27. doi: 10.1007/s11523-015-0394-5.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: January 11, 2011
• First Submitted That Met QC Criteria: January 17, 2011
• First Posted (Estimate): January 19, 2011

Study Record Updates

• Last Update Posted (Estimate): March 6, 2013
• Last Update Submitted That Met QC Criteria: March 5, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: Ovarian cancer; advanced solid tumor; Primary peritoneal cancer; Fallopian tube cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Peritoneal Diseases; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Digestive System Neoplasms; Endocrine Gland Neoplasms; Fallopian Tube Diseases; Abdominal Neoplasms; Neoplasms; Ovarian Neoplasms; Fallopian Tube Neoplasms; Peritoneal Neoplasms; Carcinoma, Ovarian Epithelial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Gemcitabine; Carboplatin; Paclitaxel; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: 2866-US-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No