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Crolibulin and Cisplatin in Treating Patients with Recurrent or Metastatic Solid Tumors That Cannot Be Removed by Surgery

Trial Status: Complete

This partially randomized phase I / II trial studies the side effects and the best dose of crolibulin and cisplatin when given together and to see how well they work in treating patients with solid tumors that have come back or spread to other parts of the body and cannot be removed by surgery. Drugs used in chemotherapy, such as crolibulin and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether cisplatin is more effective with or without crolibulin in treating solid tumors.

Inclusion Criteria

  • Pathologic confirmation of cancer by the Laboratory of Pathology, National Cancer Institute (NCI)
  • Phase I: Diagnosis of recurrent, metastatic or primary unresectable solid tumor that does not have curative standard treatment
  • Phase II : Diagnosis of recurrent, metastatic or primary unresectable ATC, including ATC as part of a thyroid carcinoma of another histologic subtype
  • Measurable disease at presentation with disease measurable by RECIST required in the phase II cohort
  • A life expectance of at least 3 months as evidenced by Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Last dose of chemotherapy or experimental therapy more than 4 weeks (6 weeks in the case of nitrosourea) prior to enrollment date; unless the last therapy consisted of an oral agent whose average half life is known to be less than 48 hours in which case only 2 weeks need to have elapsed; regardless of the therapy, any toxicity greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 from previous anti-cancer therapy must have been resolved
  • Last radiotherapy treatment 4 weeks prior to starting treatment with this protocol – with the exception of palliative radiotherapy – and there must be sites of measurable disease that did not receive radiation
  • Total bilirubin < 1.5 x upper limit of reference range (ULRR), unless the patient meets the criteria for Gilbert’s syndrome
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP): all three < 2.5 x ULRR, or < 5 x ULRR if judged by the investigator to be related to liver metastases
  • Serum creatinine =< ULRR or creatinine clearance >= 50 mL/minute (calculated by Cockcroft-Gault formula or measured in a timed urine collection)
  • Serum calcium below the CTCAE grade 1 upper limit (11.5 mg/dL or 2.9 mmol/L); in cases where the serum calcium is below the normal range, the calcium adjusted for albumin is calculated and substituted for the measured value
  • Serum potassium greater than the lower limit of normal (LLN) and < 5.5 mmol/L
  • Serum magnesium greater than the LLN and < 3.0 mg/dL or 1.23 mmol/L
  • Absolute neutrophil count >= 1000/mm^3
  • Platelet count >= 100,000/mm^3
  • Prothrombin time (PT) =< 4 seconds above upper limit of normal (ULN) and partial thromboplastin time (PTT) =< 10 seconds above ULN
  • Ability to understand and sign an informed consent document
  • Provision of informed consent prior to any study-related procedures
  • Negative pregnancy test for women of childbearing potential
  • Ability and willingness to follow the guidelines of the clinical protocol including visits to NCI, Bethesda, Maryland for treatment and follow up visits
  • Female patients must be one year post-menopausal, surgically sterile, or using an acceptable method of contraception during and continued after the last dose of study medications (oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device or tubal ligation); male patients must be surgically sterile or using an acceptable method of contraception during their participation in this study; contraceptive use will continue for at least two months after the last dose of study medication

Exclusion Criteria

  • Patients with cancer potentially curable by surgical excision alone or patients who have not received therapy that might be considered standard and potentially curable
  • Evidence of severe or uncontrolled systemic disease or any concurrent condition – including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, unstable hypertension, seizure disorder, or psychiatric illness – which in the Investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol
  • Untreated brain metastases (or local treatment of brain metastases within the last three months)
  • During Phase II enrollment: prior therapy with cisplatin with the exception of when given concurrently with radiation therapy (cisplatin will be allowed as prior therapy during Phase I enrollment)
  • Women who are currently pregnant or breast-feeding
  • During Phase II enrollment: the presence of a second malignancy within the last 2 years, other than squamous cell carcinoma of the skin or in situ cervical cancer; cancer survivors who have been free of disease for at least two years can be enrolled in this study
  • Patients with evidence of a bleeding diathesis that cannot be corrected with standard therapy or factor replacement
  • Any unresolved toxicity greater than CTCAE grade 1 (except alopecia, and certain other unresolved CTCAE grade 2 toxicities including bone marrow hypocellularity, lymphopenia, infusion-related reaction, infusion site extravasation, injection site reaction, portal vein hypertension, obesity) from previous anti-cancer therapy; patients with grade 1 neuropathy will be evaluated on a case by case basis for entry into study; pre-chemotherapy medical conditions will be taken into consideration
  • Major surgery with incompletely healed surgical incision before starting study therapy
  • Clinically significant cardiovascular event (e.g. myocardial infarction, superior vena cava syndrome [SVC], New York Heart Association [NYHA] classification of heart disease >= 2 within 3 months before entry); or presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia
  • History of arrhythmia (multifocal premature ventricular contractions PVCs), bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia; atrial fibrillation, controlled on medication, is not excluded
  • Patients with a left ventricular ejection fraction less than the institutional lower limit of normal
  • History (within the last 6 months) or presence of stroke/cerebrovascular accident
  • Corrected QT (QTc) prolongation with other medications; if the medication can be discontinued and an alternative medication started that does not cause QTc prolongation, the patient would be eligible; if no alternative medication is available and the medication cannot be discontinued for medical reasons, then the patient would not be eligible
  • Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40 years of age
  • Presence of left bundle branch block (LBBB)
  • QTc with Fridericia’s correction that is not measurable, or >= 480 msec on screening electrocardiogram (ECG); (Note: if a patient has a QTc interval >= 480 msec on screening ECG, the screen ECG may be repeated twice [at least 24 hours apart]; the average QTc from the three screening ECGs must be < 480 msec in order for the patient to be eligible for the study); patients who are receiving a drug that has a risk of QTc prolongation are excluded if QTc is >= 460 msec
  • Concurrent medication that may cause QTc prolongation or induce Torsades de Pointes
  • Crolibulin is a substrate of cytochrome P450 (CYP)2C8, CYP2C9, CYP2C19 and CYP3A4; strong inducers and inhibitors of these enzymes will constitute concomitant medications that are prohibited during the study; these medications include but are not limited to: for CYP2C8, montelukast and trimethoprim, for CYP2C9, lovastatin and sertraline, for CYP2C19, fluoxetine, ketoconazole, pantoprazole, omeprazole, rabeprazole, and ticlopidine, for CYP3A4, itraconazole, clarithromycin, erythromycin, telithromycin, and verapamil
  • Hypertension not controlled by medical therapy (systolic blood pressure greater than 150 mm Hg or diastolic blood pressure greater than 100 mm Hg)


National Cancer Institute Medicine Branch
Contact: James L. Gulley
National Institutes of Health Clinical Center
Contact: James L. Gulley
Phone: 301-496-4916

New York

New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Contact: Tito Fojo
Phone: 301-402-1359


I. To assess the safety and dose-limiting toxicities (DLTs) of crolibulin given on days 1, 2, and 3 with cisplatin given on day 1 of a 21-day cycle in adults with solid tumors (recurrent, metastatic, or primary unresectable) during dose escalations in order to establish the maximum tolerated doses (MTD) of the drug combination in patients with locally advanced or metastatic cancer, including anaplastic thyroid cancer (ATC). (Phase I)

II. To assess the duration of progression-free survival (PFS, defined as the length of time during and after treatment in which a patient is living with a disease that does not progress by Response Evaluation Criteria in Solid Tumors [RECIST] criteria) and, of somewhat less importance, to determine the tumor response rate (RR) by RECIST criteria in adults with a diagnosis of ATC treated with crolibulin given on days 1, 2, and 3 with cisplatin given on day 1 of a 21-day cycle at the MTD (discovered in Phase I) as compared to the response rate for cisplatin alone given on day 1 of a 21-day cycle. (Phase II)


I. To assess the activity of crolibulin given on days 1, 2, and 3 with cisplatin given on day 1 of a 21-day cycle in adults with cancer by determining: tumor growth rate constant; the incidence of medically necessary interventions (including tracheostomy and gastrostomy) in patients treated with both regimens.

II. Evaluate the mitotic index of tumor specimens using immunohistochemical techniques.

III. Examine by immunohistochemistry or immunoblotting: v-raf murine sarcoma viral oncogene homolog B (BRAF), vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), tumor protein p53 (TP53), proliferating cell nuclear antigen (PCNA)/Ki67, thyroglobulin 3 (TG3), excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), and aurora kinases as possible markers of tumor proliferation; BRAF V600E mutations will be identified by molecular pathology.

IV. The above markers will be correlated with the results of 3'-deoxy-3'-[18F] fluorothymidine (FLT)-positron emission tomography (PET); in a subset of patients pre- and post-treatment studies will be conducted to query whether a reduction in standardized uptake value (SUV) correlates with eventual response to therapy.

V. Evaluate tumor specimen microvascular density using anti-cluster of differentiation (CD)31 immunohistochemical staining.

VI. These findings will be correlated with computed dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) evaluation of tumor perfusion in a subset of patients, to query whether magnetic resonance evidence of perfusion changes by DCE MRI correlate with patient response to therapy and can be used as a predictor of response to therapy with crolibulin and cisplatin.

VII. Evaluate tumor gene expression and micro ribonucleic acid (RNA) profiles and correlate these findings with patient response to treatment with the combination of crolibulin and cisplatin, in the hopes of discovering predictive markers for patient response to therapy and susceptibility of the tumor to other targeted agents.

VIII. Evaluate the effect of therapy on the tumor growth rate constant.

OUTLINE: This is a phase I, dose-escalation study of cisplatin and crolibulin followed by a phase II randomized study.

PHASE I: Patients receive cisplatin intravenously (IV) over 1 hour on day 1 and crolibulin IV over 4 hours on days 1-3. Treatment repeats every 21 days for at least 4 courses in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive cisplatin IV over 1 hour on day 1 and crolibulin IV over 4 hours on days 1-3. Treatment repeats every 21 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. Patients may continue to receive crolibulin alone in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive cisplatin IV over 1 hour on day 1. Treatment repeats every 21 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. Patients developing disease progression may cross over to Arm A.

NOTE: In patients with an objective response and stable disease for > 24 months, treatment with crolibulin repeats every 4 weeks for at least 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-4 weeks for 3-4 months and then periodically thereafter.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
NCI - Center for Cancer Research

Principal Investigator
James L. Gulley

  • Primary ID 11-C-0027
  • Secondary IDs NCI-2013-01471, 110027, 343865, P10677
  • ID NCT01240590