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ACLN 1812   |   13-173
A Phase 2 Randomized, Double-Blind Study of Dalantercept plus Axitinib Compared to Placebo plus Axitinib in Patients with Advanced Renal Cell Carcinoma

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Part 1:Primary
  1. Evaluate safety and tolerability of dalantercept plus axitinib in patients with advanced renal cell carcinoma (RCC) to determine the recommended Phase 2 dose level of dalantercept plus axitinib for Part 2
  1. Evaluate progression free survival (PFS), overall survival (OS), objective response rate (ORR = complete response [CR] + partial response [PR]), duration of response (DR), and disease control rate (DCR includes CR, PR, or stable disease [SD])
  2. Evaluate the pharmacokinetic (PK) profiles of dalantercept and axitinib when used in combination
  3. Explore association of the expression of BMP9/10, ALK1 and/or other relevant pharmacodynamic (PD) markers in archived tumor biopsy with tumor response and/or other assessments of clinical response
  4. Explore association of serum pharmacodynamic (PD) biomarkers with assessments of response
Part 2:Primary
  1. To determine whether treatment with dalantercept plus axitinib prolongs progression free survival (PFS) compared to placebo plus axitinib in patients with advanced RCC
  1. Determine the PFS for the subgroups of patients who had 2 or more prior lines of anticancer therapy receiving dalantercept plus axitinib vs. placebo plus axitinib
  2. Evaluate safety and tolerability of dalantercept plus axitinib
  3. Evaluate overall survival (OS), objective response rate (ORR), duration of response (DR), and disease control rate (DCR)
  4. Explore association of the expression of BMP9/10, ALK1 and/or other relevant pharmacodynamic (PD) biomarkers in archived tumor biopsy with tumor response and/or other assessments of clinical response
  5. Explore association of serum pharmacodynamic (PD) biomarkers with assessments of response

Inclusion Criteria
  1. Age ≥ 18 years.
  2. Histologically confirmed, advanced, predominantly clear cell renal cell carcinoma (RCC).
  3. Part 1: Progression of disease following up to three lines of prior therapy, including at least one approved VEGF receptor tyrosine kinase inhibitor (TKI) for RCC. Adjuvant therapy is permitted as one line of prior therapy.
  4. Part 2: Progression of disease following one VEGF pathway inhibitor for RCC (sunitinib, pazopanib, sorafenib, bevacizumab, tivozanib, or cabozantinib) inclusive of adjuvant therapy if there was documented disease progression during treatment. Patients may have received one additional line of an approved mTOR kinase inhibitor (everolimus, temsirolimus). Prior exposure to investigational and/or approved anticancer immune therapies is permitted.
  5. A minimum of 1 week since the last dose of prior therapy (a minimum of 4 weeks since anticancer immune therapy or bevacizumab +/- interferon).
  6. Measurable disease that is evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix 1).
  7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 2).
  8. Life expectancy of at least 12 weeks.
  9. Clinical laboratory values that meet the following criteria within 72 hours prior to study day 1:
    • Hematology (in the absence of hematopoietic growth factor support):
      • Absolute neutrophil count (ANC) ≥ 1,500 /μL (≥ 1.5 x 109 /L).
      • Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
      • Platelet count ≥ 100,000 /μL (≥ 100 x 109/L).
    • Measured or calculated creatinine clearance, using the Cockcroft-Gault formula, (Appendix 5) ≥ 40 mL/min.
    • Total bilirubin ≤ 1.2 x upper limit of normal (ULN). Patients with confirmed Gilberts Syndrome may have bilirubin levels up to 3.0 mg/dL.
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present).
    • Serum albumin ≥ 3.0 g/dL (≥ 30 g/L).
    • Sodium ≥ 133 mEq/L (≥ 133 mmol/L).
    • Urinary protein < 2+ by urine dipstick or urinalysis. If ≥ 2+, then patient may be enrolled if 24-hour urine protein < 2 g/24hr.
  10. Females of child bearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥ 24 consecutive months) must have negative urine or blood pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation. Males must agree to use a latex condom during any sexual contact with females of child-bearing potential while participating in the study and for 12 weeks following the last dose of dalantercept, even if he has undergone a successful vasectomy. Patients must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of dalantercept.
  11. Ability to adhere to the study visit schedule, and to understand and comply with protocol requirements.
  12. Signed written informed consent.

Exclusion Criteria
  1. Clinically significant pulmonary, endocrine, neurologic, hematologic, gastrointestinal (GI) autoimmune or genitourinary disease unrelated to RCC that in the judgment of the investigator should preclude treatment with dalantercept or axitinib.
  2. Clinically significant cardiovascular risk including:
    • Ejection fraction (EF) ≤ 50% by echocardiogram (ECHO). Multi-gated acquisition scan (MUGA) should be obtained to estimate EF if quality of ECHO is not good.
    • Presence of grade 2 pericardial effusion on baseline ECHO.
    • Significant history of congestive heart failure (CHF) defined as New York Heart Association (NYHA) class II-IV (Appendix 3).
    • Hospitalization for CHF (any NYHA class) within 6 months of study day 1.
    • Active coronary artery disease [e.g., myocardial infarction (MI), uncontrolled angina], peripheral vascular disease, cerebrovascular disease [e.g., transient ischemic attack (TIA), stroke], bypass surgery, angioplasty, or vascular stenting within 12 months prior to study day 1. Worsening symptoms attributable to cardiac or vascular disease and no new findings on cardiac evaluation (e.g., clinical, stress test, etc.) within 3 months prior to study day 1.
    • Deep vein thrombosis (DVT) including tumor thrombus within 6 months of study day 1.
    • Significant arrhythmia or electrophysiologic disease including placement of implantable cardioverter defibrillator (ICD), atrial fibrillation with uncontrolled rate or prolonged QTc interval > 450 ms for men and > 470 ms for women.
    • Patients receiving cardiac medications should be on stable doses for at least 1 week prior to study day 1
    • Uncontrolled hypertension defined as systolic blood pressure (BP) ≥ 150 mm Hg or diastolic BP ≥ 95 mm Hg. Patients with a history of hypertension must be well-controlled (BP < 150/95) upon study entry using a stable regimen of anti-hypertensive therapy.
  3. Known CNS metastases or leptomeningeal disease.
    • For Part 1, patients with CNS metastases treated with whole brain radiotherapy, gamma knife, and/or surgery who are considered stable by CNS imaging and are not being treated with corticosteroids 6 weeks prior to study day 1 may be enrolled.
    • For Part 2, patients with CNS metastases treated with stereotatic radio-surgery (SRS), and/or surgery who are considered stable by CNS imaging for at least 2 months prior to enrollment and are not being treated with corticosteroids to manage their CNS disease within 4 weeks prior to study day 1 may be enrolled.
  4. Active GI bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia, or melena within 3 months prior to study day 1 without evidence of resolution documented by endoscopy or colonoscopy.
  5. Any active malignancy, other than RCC, for which chemotherapy or other anti-cancer therapy is indicated. Patients with adequately treated non-melanoma skin cancer, or in situ cancer are permitted. Patients with other cancers from which they have been disease-free for at least 5 years will be permitted.
  6. Any lesion invading or having encasement = 180 degrees around the wall of a major blood vessel as assessed by computed tomography (CT) scan and/or magnetic resonance imaging (MRI).
  7. Radiotherapy within 2 weeks prior to study day 1.
  8. Lack of recovery from toxic effects of previous treatment for RCC to ≤ grade 1 with the exception of alopecia, unless stabilized under adequate medical control.
  9. Systemic steroids or immunosuppressive agents within 1 week of study day 1 (with the exception of corticosteroids for CNS disease, see Exclusion #3, or physiologic doses of corticosteroids) or biologic anti-inflammatory immune modulating agents (e.g. infliximab) within 4 weeks of study day 1.
  10. Patients undergoing renal dialysis.
  11. Major surgery within 4 weeks prior to study day 1 (patients must have recovered completely from any previous surgery prior to study day 1).
  12. Any active infection requiring antibiotic therapy within 1 week of study day 1.
  13. Anti-coagulation therapy. Aspirin, other anti-platelet agents, and low molecular weight heparin are permitted unless the investigator deems the patient is at a significant risk for bleeding.
  14. Current use or anticipated inability to avoid strong CYP3A4/5 inhibitors or inducers (please refer to the Inlyta® [axitinib] prescribing information) during participation in the study.
  15. Peripheral edema requiring medical intervention within 2 weeks prior to study day 1.
  16. BMI < 16 kg/m2.
  17. Clinically significant active pulmonary risk including pulmonary hypertension and pulmonary edema within 12 months of study day 1 or pulmonary embolism within 6 months of study day 1.
  18. Bleeding diathesis including clinically significant platelet disorders, or active hemoptysis (defined as bright red blood of ≥ 1/2 teaspoon [2.5 mL] in any 24 hour period) within 6 months prior to study day 1. For clinically significant epistaxis within 4 weeks prior to study day 1, no risk of further bleeding must be clearly documented.
  19. Known history of hereditary hemorrhagic telangiectasia (HHT).
  20. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections or positive human immunodeficiency virus (HIV) antibody results. Patients with sustained virologic response to HCV treatment or immunity to HBV from prior infection without cirrhosis may be included.
  21. History of severe (defined as ≥ grade 3, using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0 [NCI-CTCAE] v4 current active minor version) allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients (10 mM Tris buffered saline) in the investigational agent.
  22. Any prior treatment with dalantercept or any other agent targeting ALK1 pathway.
  23. Any prior treatment with axitinib.
  24. A morbidity (per the Inlyta® [axitinib] prescribing information) that would require starting a patient at a reduced dose of axitinib.
  25. Treatment with another investigational drug (with the exception of anticancer immune therapy) or device, or approved therapy for investigational use, within 5 times the half-life of the drug or within 3 weeks prior to study day 1 if the half-life is not known.
  26. Pregnant or lactating female patients.

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