A Phase II Evaluation of Dalantercept (NSC #75172, IND #116598), a Novel Soluble Recombinant Activin Receptor-Like Kinase 1 (ALK-1) Inhibitor Receptor Fusion Protein, in the Treatment of Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma
- recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal
carcinoma with histologic documentation of the original primary tumor.
- measurable disease as defined by RECIST 1.1. Measurable disease is defined as at
least one lesion that can be accurately measured in at least one dimension (longest
diameter to be recorded).
- at least one "target lesion" to be used to assess response on this protocol as
defined by RECIST 1.1 (Section 8.1).
- received one prior platinum-based chemotherapeutic regimen for management of primary
disease containing carboplatin, cisplatin, or another organoplatinum compound. This
initial treatment may have included intraperitoneal therapy, consolidation,
non-cytotoxic agents or extended therapy administered after surgical or non-surgical
- one additional cytotoxic regimen for management of recurrent or persistent disease
according to the following definition is allowed: Cytotoxic regimens include any
agent that targets the genetic and/or mitotic apparatus of dividing cells, resulting
in dose-limiting toxicity to the bone marrow and/or gastrointestinal mucosa.
- patients who have received only one prior cytotoxic regimen (platinum-based regimen
for management of primary disease), must have a platinum-free interval of less than
12 months, or have progressed during platinum-based therapy, or have persistent
disease after a platinum-based therapy.
- GOG Performance Status of 0, 1, or 2 (for patient who received one prior regimen; a
GOG Performance Status of 0 or 1 (for patients who received two prior regimens).
- not eligible for higher priority GOG protocol of one exists (e.g., active phase III
protocol for same patient population).
- no active infection requiring antibiotics (with the exception of uncomplicated UTI).
- hormonal therapy directed at the malignant tumor must be discontinued at least one
week prior to registration. Continuation of hormone replacement therapy is
- prior therapy directed at the malignant tumor, including immunologic agents, must be
discontinued at least three weeks prior to registration. Therapy with nitrosoureas or
Mitomycin must be discontinued at least six weeks prior to registration.
- prior radiation therapy must be discontinued at least four weeks prior to
- at least 4 weeks must have elapsed since the patient underwent any major surgery
(e.g., major: laparotomy, laparoscopy) There is no delay in treatment for minor
procedures (e.g., central venous access catheter placement).
- Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl. Platelets
greater than or equal to100,000/mcl.
- Hemoglobin greater than or equal to 9 g/dl.
- Creatinine less than or equal to 1.5 x institutional upper limit normal (ULN). Sodium
greater than or equal to 130 mEq/L (CTCAE v. 4, grade 0 or 1).
- Urine Protein: Urine protein should be screened by urinalysis. If protein is 2+ or
higher, 24-hour urine protein should be obtained and the level should be <1000 mg
(<1.0 g/24 hrs) for patient enrollment.
- Bilirubin less than or equal to 1.5 x ULN. ALT and AST less than or equal to 3 x
ULN. Alkaline phosphatase less than or equal to 3 x ULN.
- Albumin greater than or equal to 3 (CTCAE v. 4, grade 0 or 1).
- PT such that international normalized ratio (INR) is less than or equal to 1.5 x ULN
(or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of
therapeutic warfarin) and PTT less than or equal to 1.5 x ULN.
- Left ventricular ejection fraction (LVEF) greater than 50% (measured by
echocardiogram or MUGA [multi-gated acquisition] scan).
- negative pregnancy test
- 18 years or older.
- non-cytotoxic therapy for management of recurrent or persistent disease. Patients
are allowed to receive, but are not required to receive, biologic (non-cytotoxic)
therapy as part of their primary treatment regimen.
- previous treatment with dalantercept or any other anti-ALK1 (activin receptor-like
kinase 1) agent.
- history of other invasive malignancies, with the exception of non-melanoma skin
cancer and other specific malignancies previously noted, if there is any evidence of
other malignancy being present within the last three years.
- previous cancer treatment contraindicates this protocol therapy.
- prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER THAN for
the treatment of ovarian, fallopian tube, or primary peritoneal cancer within the
last three years; prior radiation for localized cancer of the breast, head and neck,
or skin is permitted, provided that it was completed more than three years prior to
registration, and the patient remains free of recurrent or metastatic disease.
- prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of
ovarian, fallopian tube, or primary peritoneal cancer within the last three years are
excluded. Patients may have received prior adjuvant chemotherapy for localized breast
cancer, provided that it was completed more than three years prior to registration,
and that the patient remains free of recurrent or metastatic disease.
- history of primary endometrial cancer excluded unless all of the following conditions
are met: Stage not greater than I-B; no more than superficial myometrial invasion,
without vascular or lymphatic invasion; no poorly differentiated subtypes, including
papillary serious, clear cell or other FIGO Grade 3 lesions.
- history or evidence upon physical exam of CNS disease, including primary brain tumor,
seizures not controlled with standard medical therapy or any brain metastases.
- Serious or non-healing wound, ulcer or bone fracture.
- History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
within 6 months.
- Patients requiring parenteral hydration or parenteral/total parenteral nutrition.
- Patients with:
- Active bleeding (e.g., active hemoptysis, defined as bright red blood of greater
than or equal to ½ teaspoon [2.5 ml] in any 24 hour period within 2 weeks prior
to registration or gastrointestinal bleeding within 3 months prior to
- Hereditary hemorrhagic telangiectasia (HHT)
- Platelet function abnormality,
- Autoimmune or hereditary hemolysis
- Coagulopathy, or
- Tumor involving major vessels (defined as any lesion invading or abutting the
wall [i.e., no fat plane evident] of major blood vessels as assessed by CT or
- Patients receiving treatment with full dose aspirin (325mg oral daily), clopidogrel
(Plavix) or dabigatran (Pradaxa).
- Patients with peripheral edema greater than or equal to Grade 1, within 4 weeks of
- Patients with clinically significant cardiovascular disease:
- Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mm
Hg despite antihypertensive medications
- Evidence of hypertrophic cardiomyopathy
- New York Heart Association (NYHA) Class II or greater congestive heart failure
(CHF). (Appendix II)
- Any of the following within 6 months prior to study registration:
- Bypass surgery
- Stent placement
- Myocardial infarction
- Acute coronary syndrome/unstable angina
- Hospitalization for CHF
- Serious cardiac arrhythmia requiring medication. This does not include
asymptomatic, atrial fibrillation with controlled ventricular rate.
- Prolonged QTc interval > 450 ms.
- Prior anthracycline cumulative dose > 450 mg/m2.
- History of severe (National Cancer Institute-Common Terminology Criteria for Adverse
Events [NCI-CTCAE] v.4.0 ≥ grade 3) allergic or anaphylactic reaction or
hypersensitivity to recombinant proteins or Tris buffered saline.
- Patients with or with anticipation of invasive procedures as defined below:
- Major surgical procedure, open biopsy or significant traumatic injury within 28
days prior to the first date of dalantercept therapy.
- Major surgical procedure anticipated during the course of the study. This
includes, but is not limited to abdominal surgery (laparotomy or laparoscopy)
prior to disease progression as defined in section 8.3, such as colostomy or
enterostomy reversal or secondary cytoreductive surgery. Please consult with the
Study Chair prior to patient entry for any questions related to the
classification of surgical procedures.
- Minor surgical procedures, fine needle aspirates, or core biopsies within 7 days
prior to the first date of dalantercept therapy.
- History of syndrome of inappropriate antidiuretic hormone secretion (SIADH).
- History of positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface
antigen (HBsAg) or HBV core antibody, or human immunodeficiency virus (HIV) antibody
- Clinically significant active pulmonary risk including pulmonary hypertension,
pulmonary embolism, or history of pulmonary edema.