Clinical Trials /

Recombinant Albumin Fusion Protein sEphB4-HSA in Treating Patients With Metastatic or Recurrent Solid Tumors

NCT01642342

Description:

This study is about an experimental drug called sEphB4-HSA (recombinant albumin fusion protein sEphB4-HSA). This research study will be the first time sEphB4-HSA is given to people. sEphB4-HSA prevents tumor cells from multiplying and blocks several compounds that promote the growth of blood vessels that bring nutrients to the tumor. sEphB4-HSA has shrunk colon, lung, breast, glioma, melanoma, prostate and Kaposi's sarcoma tumors in mice

Related Conditions:
  • Colorectal Carcinoma
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Recombinant Albumin Fusion Protein sEphB4-HSA in Treating Patients With Metastatic or Recurrent Solid Tumors
  • Official Title: A First-In-Human Phase I Study of sEphB4-HSA in Patients With Advanced Solid Tumors With Expansion at the Maximum Tolerated Dose (MTD) or Recommended Phase II Dose (RP2D).

Clinical Trial IDs

  • ORG STUDY ID: 0C-11-3
  • SECONDARY ID: NCI-2012-00971
  • NCT ID: NCT01642342

Conditions

  • Unspecified Adult Solid Tumor, Protocol Specific

Interventions

DrugSynonymsArms
recombinant albumin fusion protein sEphB4-HSAWeekly Treatment (sEphB4-HSA)

Purpose

This study is about an experimental drug called sEphB4-HSA (recombinant albumin fusion protein sEphB4-HSA). This research study will be the first time sEphB4-HSA is given to people. sEphB4-HSA prevents tumor cells from multiplying and blocks several compounds that promote the growth of blood vessels that bring nutrients to the tumor. sEphB4-HSA has shrunk colon, lung, breast, glioma, melanoma, prostate and Kaposi's sarcoma tumors in mice

Detailed Description

      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.

      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
      schedules:

        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 weeks treatment - administered on days 1 and 15. Courses repeat every 28 days in
           the absence of disease progression or unacceptable toxicity.

        3. Every 3 weeks treatment - administered on day 1. Courses repeat every 21 days in the
           absence of disease progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Weekly Treatment (sEphB4-HSA)ExperimentalPatients receive recombinant albumin fusion protein sEphB4-HSA IV over 60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • recombinant albumin fusion protein sEphB4-HSA
Every 2 Weeks Treatment (sEphB4-HSA)ExperimentalPatients receive recombinant EphB4-HSA fusion protein IV over 60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • recombinant albumin fusion protein sEphB4-HSA
Every 3 Weeks Treatment (sEphB4-HSA)ExperimentalPatients receive recombinant EphB4-HSA fusion protein IV over 60 minutes on days 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • recombinant albumin fusion protein sEphB4-HSA

Eligibility Criteria

        Inclusion Criteria:

          -  For expansion Cohort A: 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. Measurable disease required.

          -  For expansion Cohort B: 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). Measurable disease required.

          -  Must agree, as part of the informed consent, to provide blood and tumor samples for
             molecular correlates, pharmacokinetics and pharmacodynamics. Patients in 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 & 4
             must have tumor sites that are accessible for tumor biopsy and must agree to undergo a
             pre-treatment and post-treatment biopsy.

          -  Must have an Eastern Cooperative Oncology Group (ECOG) performance score of 0-1

          -  Life expectancy of at least 12 weeks

          -  Patients or their legal representatives must be able to comprehend and provide written
             informed consent

          -  White blood count (WBC) >= 3,000/μl

          -  Absolute neutrophil count (ANC) >= 1,500/μl

          -  Platelet count >= 100,000/μl (except in hepatocellular carcinoma patients with portal
             hypertension for whom a platelet count of >= 70,000/μl is allowed)

          -  Serum creatinine =< 1.5 X upper limit of normal (ULN) for reference lab

          -  Creatinine Clearance of >= 60 (as calculated by Cockcroft-Gault formula

          -  Serum bilirubin =< 1.5 mg/dL

          -  Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =< 3X
             the ULN for the reference lab (=< 5X the ULN if there is evidence of hepatic
             involvement by malignant disease)

          -  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 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 study
             drug

          -  Patients with hepatitis B infection must be on appropriate antiviral therapy

          -  For cohort B, group 1: Non-small cell lung cancer:

               -  Must have advanced non-small cell lung cancer with mutant KRAS

               -  Must have failed a minimum of one previous line of chemotherapy for advanced
                  disease

          -  For cohort B, group 2: Pancreatic cancer:

               -  Must have failed a minimum of one previous line of therapy for advanced disease

          -  For cohort B, group 3: Colorectal cancer:

               -  Must have colorectal adenocarcinoma that harbor a KRAS mutation

               -  Must have failed a minimum of one previous line of chemotherapy

          -  For cohort B, group 4: Head and neck squamous cell cancer:

               -  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.

          -  For cohort B, group 5: Mesothelioma:

               -  Must have histologically or cytologically proven diagnosis of malignant
                  mesothelioma; both pleural and peritoneal mesothelioma are allowed

               -  Must have failed a minimum of one previous line of systemic therapy for advanced
                  disease

          -  For 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 HCC (evidence of arterial phase enhancement with corresponding
                  venous or delayed phase wash out).

               -  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

               -  Patients are not required to have failed Sorafenib

          -  For cohort B, group 7: Gallbladder cancer or cholangiocarcinoma:

               -  Must have failed a minimum of one previous line of systemic therapy for advanced
                  disease. If 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.

        Exclusion Criteria:

          -  Undergoing or have undergone in the past 28 days any other therapy for their cancer,
             including radiation and adjuvant therapy

          -  Major systemic infection requiring antibiotics 72 hours or less prior to first dose of
             study drug

          -  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

          -  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

          -  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

          -  Pregnant or lactating

          -  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

          -  Any active bleeding in the last =< 4 weeks or have an otherwise known bleeding
             diathesis

          -  QTcF (Fridericia Correction Formula) > 480 on 2 out of 3 EKG's (if first EKG is < 480,
             no need to repeat, if first EKG is > 480 repeat twice for a total of 3 EKG's)

          -  For cohort B, group 1: Non-small cell lung cancer:

               -  Must not have clinically significant active hemoptysis

          -  For cohort B, group 4: Head and neck squamous cell cancer:

               -  Must not have evidence of major vessel involvement or encasement by tumor

          -  For cohort B, group 6: Hepatocellular Carcinoma:

               -  Child Pugh score > 7

               -  Ascites that is not medically controlled or that required a therapeutic
                  paracentesis within last 3 months

               -  Any episode of hepatic encephalopathy within the previous 6 months

               -  Variceal bleeding within last 6 months

               -  Patients with evidence of portal hypertension must have had an EGD within last
                  year with appropriate treatment of esophageal varices as per standard of care
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Toxicities observed at each dose level utilizing the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0
Time Frame:At least 4 weeks after the start of the first course
Safety Issue:
Description:Summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by CTCAE and nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize toxicities and side effects by dose and by course.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Southern California

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