Details

Details

Title A Four Part, Phase 1, Multi-center, Open-label Study of DKN-01 in Combination with Weekly Paclitaxel

IRB HCP2215

CC 031520C

Hospital Main Campus

Phase Phase 1

Disease Esophageal

Drug Paclitaxel

Description

Description

Primary Objective
  • To characterize the safety and tolerability of DKN-01 in combination with weekly paclitaxel in patients with refractory/recurrent esophageal or gastro-esophageal junction cancer
Secondary Objectives
  • To estimate the overall response rate (ORR) of patients with refractory/recurrent esophageal or gastro-esophageal junction cancer treated with DKN-01 in combination with paclitaxel.
  • To estimate progression free survival (PFS), duration of response (DoR), and overall survival (OS) of patients with refractory/recurrent esophageal or gastro-esophageal junction cancer treated with DKN-01 in combination with paclitaxel.
  • To characterize the pharmacokinetics of DKN-01 in combination with paclitaxel in patients with refractory/recurrent esophageal or gastro-esophageal junction cancer.
Exploratory Objectives
  • To evaluate Dkk-1 associated targets and downstream elements (e.g., Dkk-1 and CA-IX) expression in tumor tissue relative to clinical outcomes (e.g., PFS and ORR)
Inclusion Criteria

Inclusion Criteria

Advanced Esophageal Malignancies:Parts A and B:
  • Patients with histologically confirmed recurrent or metastatic esophageal or gastro-esophageal junction squamous cell or adenocarcinoma.
Part C:
  • Patients with histologically confirmed recurrent or metastatic esophageal or gastro-esophageal junction adenocarcinoma.
Part D:
  • Patients with histologically confirmed recurrent or metastatic esophageal squamous cell cancer.
DKN-01 Monotherapy Substudy:
  • Patients with histologically confirmed recurrent or metastatic esophageal or gastro-esophageal junction squamous cell or adenocarcinoma.
  • Patients not eligible to receive paclitaxel for any reason, including but not limited to:
    • Pre-existing comorbidities (e.g. clinically significant peripheral neuropathy)
    • Intolerance or known hypersensitivity to paclitaxel or any of its excipients (e.g. Cremophor, alcohol)
    • Known resistance to paclitaxel
Part A, B, C and D and DKN-01 Monotherapy Substudy
  • Patients must have sufficient paraffin-embedded tumor tissue available for submission. Paraffin embedded tissue from prior surgical resection or from a diagnostic biopsy is acceptable.
  • Patients must be refractory or intolerant to at least one prior standard therapy(ies) for metastatic or locally advanced disease
    • If prior therapy consisted of palliative chemoradiation therapy it will be considered one line of therapy.
    • Prior treatment with paclitaxel as part of a definitive therapy regimen is acceptable provided the patient is not intolerant of paclitaxel. Patients who are not eligible to receive paclitaxel (see inclusion criteria #1e) will be allowed to receive single agent DKN-01.
General:
  1. Patients must have one or more tumors measurable on radiographic imaging as defined by RECIST. Patients with evaluable but not measurable disease or if there are areas of suspicious uptake on FDG PET consistent with tumor metabolism may be considered candidates for enrollment with the approval of the medical monitor. Pleural effusions or ascites alone without pathologic proof of tumor will not be considered eligible for inclusion.
  2. Ambulatory patients ≥ 30 years of age.
  3. Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. Performance status of 2 on the Eastern Cooperative Oncology Group (ECOG) scale may be entered upon the review and approval of the medical monitor.
  4. Have an estimated life expectancy of at least 3 months, in the judgment of the investigator.
  5. Disease-free of active second/secondary or prior malignancies for equal to or over 2 years with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in-situ" of the cervix or breast.
  6. Acceptable liver function:
    • Bilirubin ≤ 1.5 times upper limit of normal.
    • AST (SGOT), ALT (SGPT) and alkaline phosphatase ≤ 2.5 times upper limit of normal (if liver metastases are present, then ≤ 5 x ULN is allowed).
  7. Acceptable renal function:
    • Creatinine normal for age; if serum creatinine is abnormal for age the patient must have ausing the Cockcroft and Gault Method.
  8. Acceptable hematologic status:
    • Granulocyte ≥ 1500 cells/mm3.
    • Hemoglobin ≥ 9 g/dL (transfusion permitted within 30 days of study entry).
    • Platelet count ≥ 100,000 (plt/mm3).
  9. Acceptable coagulation status:
    • PT/PTT ≤ 1.2 x ULN (unless receiving anticoagulation therapy, if receiving anticoagulation therapy, eligibility will be based upon INR, see 11(b)(i)).
    • INR ≤ 1.6 (unless receiving anticoagulation therapy)
      • If receiving anticoagulant: INR ≤ 3.0 and no active bleeding, (i.e., no bleeding within 14 days prior to first dose of study therapy).
  10. For men and women of child-producing potential, the use of effective contraceptive methods during the study and for 6 months following the last dose of study drug. NOTE: Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) during the study, and must agree to use adequate contraception prior to study entry and for 6 months after their last dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  11. Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures.
  12. Provide written informed consent prior to any study specific procedures.
Exclusion Criteria

Exclusion Criteria

General:
  1. New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia.
  2. Fridericia-corrected QT interval (QTcF) > 470 msec (female) or > 450 (male), or history of congenital long QT syndrome. Any ECG abnormality that in the opinion of the investigator would preclude safe participation in the study; patients with pacemakers evaluation by a cardiologist to exclude co-existing cardiac conditions which would prohibit safe participation in the study.
  3. Active, uncontrolled bacterial, viral, or fungal infections, within 7 days of study entry requiring systemic therapy.
  4. Known to be human immunodeficiency virus (HIV) positive, have hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb) unless HCV RNA undetected/negative.
  5. History of major organ transplant (for example: heart, lungs, liver and kidney).
  6. History of autologous/ allogenic bone marrow transplant.
  7. Serious nonmalignant disease that could compromise protocol objectives in the opinion of the investigator and/or the Sponsor.
  8. Pregnant or nursing women.
  9. History of osteonecrosis of the hip or have evidence of structural bone abnormalities in the proximal femur on MRI scan that are symptomatic and clinically significant. Degenerative changes of the hip joint are not exclusionary. Screening of asymptomatic patients is not required.
  10. Symptomatic central nervous system (CNS) malignancy or metastasis. Patients with treated CNS metastases are eligible provided their disease is radiographically stable, asymptomatic, and they are not currently receiving corticosteroids and/or anticonvulsants. Radiation must have been completed at least 14 days prior to study entry. Screening of asymptomatic patients without a history of CNS metastases is not required.
  11. Clinically significant peripheral neuropathy at the time of study entry. Patients with pre-existing peripheral neuropathy (see inclusion criteria #1e) will be allowed to receive single agent DKN-01.
  12. Known osteoblastic bony metastasis. Screening of asymptomatic patients without a history of metastatic bony lesions is not required.
Medication Related:
  1. Treatment with surgery or chemotherapy within 21 days prior to study entry (42 days for nitrosoureas or mitomycin C).
  2. Treatment with low dose chemotherapy concurrent with radiation within 14 days prior to study entry.
  3. Treatment with radiation therapy within 14 days prior to study entry.
  4. Patients who are currently receiving any other investigational agent or have received an investigational agent within last 30 days of study entry or 5 half-lives, whichever is longer
  5. Previously treated with an anti-Dkk-1 therapy.
  6. Patients who have a history of hypersensitivity reactions to TAXOL® or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil). Patients who exhibit these hypersensitivities (see inclusion criteria #1e) will be eligible to receive single agent DKN-01.
  7. Significant allergy to a pharmaceutical therapy that, in the opinion of the investigator, poses an increased risk to the patient.
Lifestyle Related:
  • Active substance abuse