Ganitumab, Everolimus, and Panitumumab in Treating Patients with Refractory Solid Tumors

Status: Active

Description

This phase I trial studies the side effects and the best dose of ganitumab, everolimus, and panitumumab when given together in treating patients with solid tumors that has not responded to previous treatment. Monoclonal antibodies, such as ganitumab and panitumumab, can block the ability of tumors to grow and spread by blocking protein activity which is important for tumors to grow. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving ganitumab with everolimus and panitumumab may kill more tumor cells.

Eligibility Criteria

Inclusion Criteria

  • Histologically and/or cytologically confirmed malignant solid tumor that is refractory to standard therapies, or for which no standard therapies exist; disease must be measurable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria * For the non-small cell lung cancer (NSCLC) expanded cohort only: only histologically proven adenocarcinoma that is refractory to standard therapies
  • Karnofsky performance status of 60-100
  • Life expectancy of at least 3 months
  • Absolute neutrophil count >= 1,500/ul
  • Platelets >= 100,000/ul
  • Magnesium (triplet combination only) >= 1.8 mg/dL
  • Phosphorus >= 2.3 mg/dL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN, =< 5 x ULN if known hepatic metastases
  • Prothrombin time (PT)/international normalized ratio (INR); partial thromboplastin time (PTT) =< 1.3; =< 1.3 x ULN
  • Creatinine clearance >= 40 mL/min/m^2 by Cockroft-Gault or Modification of Diet in Renal Disease (MDRD) equation
  • Hemoglobin >= 9 g/dL; continuation of erythropoietin products is permitted; hemoglobin must be stable above 9 g/dL for at least 2 weeks without blood transfusion to maintain hemoglobin level
  • Fasting blood sugar =< 160 mg/dL; patient may be on diabetic medication to achieve glucose control * Documented fasting blood sugars =< 160 mg/dL * Diabetic subjects who have recently had their glycemic control regimens adjusted and have documented fasting blood glucose concentrations =< 160 mg/dL may be considered regardless of hemoglobin A1C (HgbA1c) value, if per investigator discretion the subject is considered to have adequate glycemic function
  • Ability to understand and the willingness to sign a written informed consent document
  • NSCLC expanded cohort only: total of 20 never smokers and non-smokers; never smokers are defined as individuals who have never smoked and non-smokers are defined as individuals with a =<10 pack year history and have quit > 15 years

Exclusion Criteria

  • Radiation therapy, hormonal therapy, biologic therapy or chemotherapy for cancer within the 28 days prior to day 1 of study drug * For the NSCLC expanded cohort only: palliative radiation therapy =<14 days of day 1 of study drug
  • Active central nervous system (CNS) metastases; magnetic resonance imaging (MRI) (or computed tomography [CT]) required within 3 months of starting treatment for all tumor types known to commonly metastasize to the brain (i.e. all tumors except pancreas, colorectal, ovarian) and for all patients with CNS symptoms that may represent CNS metastases; metastases which have been treated with radiotherapy > 2 months prior to start of protocol therapy and are asymptomatic (off steroid therapy for at least 1 month) may be included; patients must have had normal or stable (if treated, no new lesions) brain imaging (CT or MRI) within the two months prior to day 1 of study drug * For the NSCLC expanded cohort only: radiation =< 14 days prior to day 1 of study drug; subjects must be off steroids for > 14 days prior to day 1 of study drug and anticonvulsants must be discontinued
  • Inadequately controlled hypertension (defined as systolic blood pressure > 140 and/or diastolic blood pressure > 90 mmHg); initiation of antihypertensive is permitted provided adequate control is documented over at least 1 week prior to day 1 of study drug
  • Evidence of active bleeding diathesis or coagulopathy * For the NSCLC expanded cohort only: history of “blood tinged” sputum allowed
  • No warfarin therapy; low molecular weight heparin anticoagulation is permitted provided that patients have been clinically stable on anti-coagulation for at least 2 weeks prior to day 1 of study drug and meet platelet inclusion criteria; no history of active gastrointestinal (GI) bleeding or other major bleeding within previous 6 months prior to day 1 of study drug
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1 of study drug (56 days for hepatectomy, open thoracotomy, major neurosurgery) or anticipation of need for major surgical procedure during the course of the study
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to day 1 of study drug
  • Serious, non-healing wound, ulcer, or bone fracture
  • Any prior history of hypertensive crisis or hypertensive encephalopathy
  • New York Heart Association (NYHA) grade II or greater congestive heart failure
  • History of clinically significant vascular disease, including any of the following within 6 months prior to day 1 of study drug: myocardial infarction or unstable angina, percutaneous coronary intervention, bypass grafting, ventricular arrhythmia requiring medication, stroke or transient ischemic attack, symptomatic peripheral arterial disease and/or involvement of great vessels by tumor with or without vascular grafting
  • Chronic treatment with systemic steroids or another immunosuppressive agent with the following exceptions: * Intermittent steroids may be used on an as-needed basis (e.g. treatment for chemotherapy-related nausea) * Patients on physiologic replacement doses of steroids due to adrenal insufficiency for any reason may remain on these medications
  • A known history of human immunodeficiency virus (HIV) seropositivity, hepatitis C virus, acute or chronic active hepatitis B infection, or other serious chronic infection requiring ongoing treatment
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption (e.g. inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or significant small bowel resection)
  • Patient unwilling to or unable to comply with the protocol
  • Medical need for the continuous administration of any drugs which affect CYP3A4 though the use of low dose glucocorticoids (e.g. dexamethasone =< 4 mg daily or equivalent) for anorexia and /or nausea is permitted
  • History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis, or any evidence of interstitial lung disease on baseline chest CT scan * For the NSCLC expanded cohort only: scarring from previous radiation therapy or pneumonia allowed
  • Patients who are pregnant and/or lactating are excluded from this study; women of child-bearing potential and men must agree to use two forms of adequate contraception (hormonal or barrier method of birth control; abstinence) prior to day 1 of study drug, the duration of study participation and 6 months after the last dose of study drug; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study, she should inform her treating physician and study principal investigator (PI) immediately; oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study)
  • Other concurrent severe and/or uncontrolled medical, psychiatric or social conditions that could compromise the safety or compliance of treatment as so judged by treating physician * Examples include but are not limited to: ** History of severely impaired lung function defined as spirometry and diffusion capacity of carbon monoxide (DLCO) that is =< 50% of the normal predicted value and/or 02 saturation that is =< 88% at rest on room air ** Uncontrolled diabetes mellitus consistent fasting blood glucose readings > 160 mg/dL or < 50 mg/dL); use of diabetic medications is permitted ** Hyperlipidemia (total cholesterol > 300-400; triglycerides > 300); use of lipid lower lowering agents is permitted ** Other: e.g. severe infection, severe malnutrition, ventricular arrhythmias, known active vasculitis of any cause, tumor invasion of any major blood vessel, severe chronic liver or renal disease, active upper GI tract ulceration
  • No immunizations with attenuated live vaccines within one week of study entry or during study period
  • Proteinuria at screening as demonstrated by either urine protein: urine protein creatinine (UPC) ratio >= 1.0 or 24hr collection > 1g/24hr at screening
  • NSCLC cohort only: current smoker

Locations & Contacts

North Carolina

Durham
Duke University Medical Center
Status: Active
Contact: Herbert I. Hurwitz
Phone: 919-681-6006
Email: hurwi004@mc.duke.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To define the maximal tolerated dose (MTD) and/or recommended phase II dose (RPTD) for the doublet AMG 479 (ganitumab) in combination with everolimus in subjects with advanced solid tumors.

II. To define the maximal tolerated dose (MTD) and/or recommended phase II dose (RPTD) for the triplet AMG 479 in combination with everolimus and panitumumab in subjects with advanced solid tumors.

SECONDARY OBJECTIVES:

I. To describe the toxicity profile seen with these combinations.

II. To describe any signs of clinical activity, including response rate and progression free survival associated with these regimens.

TERTIARY OBJECTIVES:

I. To explore the effect of these combination therapies on the insulin-like growth factor-1 receptor (IGF-1R), mTOR, and EGFr pathways in tumor and dermal wound tissue as well with blood/urine based biomarkers.

II. To explore the effect of tumor mutations and other alterations that may predict for sensitivity or resistance to anti-IGF-1R, mTOR and EGFr combination therapies.

OUTLINE: This is a dose-escalation study.

PART I: Patients receive ganitumab intravenously (IV) over 30-120 minutes on days 1 and 15 and everolimus orally (PO) daily on days 1-28 (days 15-28 of course 1 only for patients treated on the expanded cohort). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PART II: Patients receive ganitumab IV over 30-120 minutes on days 1 and 15 and everolimus PO daily on days 1-28 and panitumumab IV over 30-90 minutes on days 1 and 15*. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients in the expanded cohort receive ganitumab or everolimus as monotherapy for 2 weeks, followed by the addition of the triplet including panitumumab on day 15 of course 1.

After completion of study treatment, patients are followed up for 30 days and then every 12 weeks thereafter.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Duke University Medical Center

Principal Investigator
Herbert I. Hurwitz

Trial IDs

Primary ID Pro00021317
Secondary IDs NCI-2013-02192
Clinicaltrials.gov ID NCT01061788