Recombinant EphB4-HSA Fusion Protein in Treating Patients with Metastatic or Recurrent Solid Tumors
Trial Status: complete
This phase I trial studies the side effects and best dose of recombinant EphB4-HSA fusion protein in treating patients with solid tumors that have spread from the primary site to other parts of the body or have come back. Recombinant EphB4-HSA prevents tumor cells from multiplying and blocks several compounds that promote the growth of blood vessels that bring nutrients to the tumor.
Inclusion Criteria
- Patient must have an advanced (metastatic or recurrent) pathologically proven solid tumor which has not responded to standard therapy or which has progressed following standard therapy for advanced disease and/or for which no standard therapy is known to be effective; patients in expansion cohort A must have accessible tumor for biopsy
- Expansion cohort B, groups 1, 2, 3, 4, 5, 6 and 7: Patients must have advanced pathologically proven mutant KRAS non-small cell lung cancer (group 1), pancreatic cancer (group 2; documentation of KRAS mutation not required), mutant KRAS colorectal cancer (group 3), head and neck squamous cell carcinoma (group 4), mesothelioma (group 5), hepatocellular cancer (group 6), and biliary carcinoma (group 7)
- Patient must agree, as part of the informed consent, to provide blood and archived tumor samples for molecular correlates, pharmacokinetics and pharmacodynamics; patients in the expansion cohort A must have tumor sites that are accessible for tumor biopsy and must agree to undergo a pre-treatment and post-treatment biopsy; patients in cohort B group 3 and 4 must have tumor sites that are accessible for tumor biopsy and must agree to undergo a pre-treatment and post-treatment biopsy; this requirement may be waived after discussion with the principal investigator as long as a minimum of 5 patients in cohort B group 3 and 10 patients in cohort B group 4 are able to undergo the required biopsies
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance score of 0-1
- Patients must have a life expectancy of at least 12 weeks
- Patients or their legal representatives must be able to comprehend and provide written informed consent
- Absolute neutrophil count (ANC) >= 1,000/μl
- Platelet count >= 100,000/μl (except in hepatocellular carcinoma patients with portal hypertension for whom a platelet count > 70,000/ul is allowed)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) for reference lab
- CrCl of >= 60 (as calculated by Cockcroft-Gault formula)
- Serum bilirubin =< 1.5 mg/dL
- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =< 3 x the ULN for the reference lab (=< 5 x the ULN if there is evidence of hepatic involvement by malignant disease)
- Patients must be recovered to grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies
- Women of childbearing potential (WOCBP) and male patients with WOCBP partner must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized; WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal; post menopause is defined as: * Amenorrhea >= 12 consecutive months without another cause or * For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL
- Women who are using oral contraceptives, other hormonal contraceptives (vagina products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential WOCBP must have a negative serum test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours prior to the start of investigational product
- Patients with hepatitis B infection must be on appropriate antiviral therapy
- Patients in expansion cohorts A and B must have measurable disease
- COHORT A: Patients must have accessible tumor sites for biopsy and must agree to pre-treatment and post-treatment biopsies
- COHORT A: All other inclusion and exclusion criteria apply
- COHORT B GROUP 1: NON-SMALL CELL LUNG CANCER: Patients must have advanced non-small cell lung cancer with mutant KRAS
- COHORT B GROUP 1: NON-SMALL CELL LUNG CANCER: Patients must have failed a minimum of one previous line of chemotherapy for advanced disease
- COHORT B, GROUP 2: PANCREATIC CANCER: Patients must have failed a minimum of one previous line of therapy for advanced disease
- COHORT B, GROUP 3: COLORECTAL CANCER: Patients must have colorectal adenocarcinoma that harbored a KRAS mutation
- COHORT B, GROUP 3: COLORECTAL CANCER: Patients must have failed a minimum of one previous line of chemotherapy
- COHORT B, GROUP 4: HEAD AND NECK SQUAMOUS CELL CANCER: Patients with head and neck squamous cell carcinoma must have failed a platinum based chemotherapy regimen that was administered for advanced disease with a palliative intent: patients treated with concurrent platinum agent and radiation as definitive therapy are not eligible unless they subsequently received another line of systemic therapy
- COHORT B, GROUP 5: MESOTHELIOMA: Patients must have histologically or cytologically proven diagnosis of malignant mesothelioma; both pleural and peritoneal mesothelioma are allowed
- COHORT B, GROUP 5: MESOTHELIOMA: Patients must have failed a minimum of one previous line of systemic therapy for advanced disease
- COHORT B, GROUP 6: HEPATOCELLULAR CARCINOMA: Patients with hepatocellular carcinoma do not need to have histologic confirmation of disease as long as they meet the radiologic criteria for diagnosis of hepatocellular carcinoma (HCC) (evidence of arterial phase enhancement with corresponding venous or delayed phase wash out)
- COHORT B, GROUP 6: HEPATOCELLULAR CARCINOMA: Patients must have advanced disease that is not amenable for resection or transplantation, and that is not treatable with liver directed modalities such as radiofrequency ablation or transarterial chemoembolization
- COHORT B, GROUP 6: HEPATOCELLULAR CARCINOMA: Patients are not required to have failed sorafenib
- COHORT B, GROUP 7: GALLBLADDER CANCER OR CHOLANGIOCARCINOMA: Patients must have failed a minimum of one previous line of systemic therapy for advanced disease
- COHORT B, GROUP 7: GALLBLADDER CANCER OR CHOLANGIOCARCINOMA: If the patient has had decompression of the biliary tree within the last 14 days, stability of the bilirubin level needs to be confirmed with two measurements that are within 5 to 7 days of each other; (the second measurement must be obtained within 7 days prior to registration); both the first and second measurement must be < 1.5 x institutional ULN (IULN); stability is defined as the second measurement being no more than one point higher than the first
Exclusion Criteria
- If they are undergoing or have undergone in the past 4 weeks (28 days) any other therapy for their cancer, including radiation therapy and adjuvant therapy
- If they have a major systemic infection requiring antibiotics 72 hours or less prior to the first dose of study drug
- If they have untreated central nervous system (CNS) metastases; patients whose CNS metastases have been treated by surgery or radiotherapy, who are no longer on corticosteroids, and who are neurologically stable may be enrolled in the dose escalation portion of the trial
- QTcF (Fridericia Correction Formula) > 480 on 2 out of 3 EKG’s (if first EKG is =< 480, no need to repeat, if first electrocardiogram [EKG] is > 480 repeat twice for a total of 3 EKG’s)
- If they have New York Heart Association (NYHA) class 3 or 4: myocardial infarction, acute coronary syndrome, diabetes mellitus with ketoacidosis or chronic obstructive pulmonary disease (COPD) requiring hospitalization in the preceding 6 months; or any other intercurrent medical condition that contraindicates treatment with sEphB4HSA or places the patient at undue risk for treatment related complications
- If they have any other condition, including mental illness or substance abuse, deemed by the investigator to be likely to interfere with a patient’s ability to sign informed consent, cooperate and participate in the study, or interferes with the interpretation of the results
- If they are pregnant or lactating
- If they are on any dose of warfarin or are on full dose anticoagulation with other agents, including low molecular weight heparin, antithrombin agents, antiplatelet agents and full dose aspirin within 7 days prior to first dose of study drug; patients on prophylactic doses of low-molecular weight heparin are allowed
- If they have had any active bleeding in the last =< 4 weeks or have an otherwise known bleeding diathesis
- Cohort specific exclusion criteria (cohorts and groups without applicable specific exclusion criteria are not listed separately and should follow the general exclusion criteria)
- COHORT B, GROUP 1: NON-SMALL CELL LUNG CANCER: Patients must not have clinical significant hemoptysis
- COHORT B, GROUP 4: HEAD AND NECK SQUAMOUS CELL CARCINOMA: Patients must not have evidence of major vessel involvement or encasement by tumor; a tumor abutting a major blood vessel may be allowed after review of scans with the radiologist and discussions with the principal investigator (PI)
- COHORT B, GROUP 6: HEPATOCELLULAR CARCINOMA: Child-Pugh score > 7
- COHORT B, GROUP 6: HEPATOCELLULAR CARCINOMA: Ascites that is not medically controlled or that required a therapeutic paracentesis within last 3 months
- COHORT B, GROUP 6: HEPATOCELLULAR CARCINOMA: Any episode of hepatic encephalopathy within the previous 6 months
- COHORT B, GROUP 6: HEPATOCELLULAR CARCINOMA: Variceal bleeding within last 6 months
- COHORT B, GROUP 6: HEPATOCELLULAR CARCINOMA: Patients with evidence of portal hypertension must have had an esophagogastroduodenoscopy (EGD) within last year with appropriate treatment of esophageal varices as per standard of care
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT01642342.
PRIMARY OBJECTIVES:
I. To establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of sEphB4-HSA.
II. To describe the dose limiting toxicities and adverse event profile of sEphB4-HSA in patients with advanced solid tumors.
III. To describe the pharmacokinetics of sEphB4-HSA.
IV. To describe the anti-tumor activity of sEphB4-HSA as manifested by responses to treatment.
V. To obtain preliminary evaluation of effect of sEphB4-HSA on absolute circulating tumor cell (CTC) numbers as compared with pre-treatment levels using pre- and during treatment CTC. Exploratory evaluation of effect of sEphB4-HSA on downstream protein mediators of the Ephrin pathway (pAKT, pSrc) and their transcriptional target genes (rgs5 and psenen) will be performed.
VI. To collect pilot information to identify a dose or doses with biologic activity. Biologic activity after treatment with sEphB4-HSA will be defined as evidence of drug-on-target effect as manifested by reduction in absolute CTC numbers. Other exploratory evaluations of drug-on-target effect such as increase in transcript levels of psenen or rgs5 may be considered in the assessment of biologic activity.
VII. To describe the anti-tumor activity in specific expansion groups of various solid tumors.
OUTLINE: This is a dose-escalation study.
Patients will be assigned to receive recombinant EphB4-HSA fusion protein intravenously (IV) over 60 minutes in one of the following treatment schedule:
1. Weekly treatment administered on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
2. Every 2 week treatment administered on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationUSC / Norris Comprehensive Cancer Center
Principal InvestigatorAnthony B El-Khoueiry
- Primary ID0C-11-3
- Secondary IDsNCI-2012-00971
- ClinicalTrials.gov IDNCT01642342