Solid TumorPhase 1/2NCT01240590
A Phase I/II Trial of Crolibulin (EPC2407) Plus Cisplatin in Adults With Solid Tumors With a Focus on Anaplastic Thyroid Cancer (ATC)
A Phase 1/2 study testing Crolibulin and Cisplatin in people with Solid Tumor and Anaplastic Thyroid Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
Background: Anaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors; chemotherapy and surgery have had no impact on local control or survival of patients, with a median survival of 3-7 months. Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Solid Tumor, Anaplastic Thyroid Cancer
- What is being tested?
- Crolibulin and Cisplatin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 27 participants
- Where
- 1 siteUnited States
- Study dates
- 26 Jan 2011to 31 Dec 2016
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 anaplastic thyroid cancer (ATC), including ATC as part of a thyroid carcinoma of another histologic subtype.
- Measurable disease at presentation with disease measurable by Response Evaluation Criteria in Solid Tumors (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.
- Age greater than or equal to 18 years
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- 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 in 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.
- Organ and marrow function as defined:
- total bilirubin < 1.5 times the 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 times the ULRR, or < 5 times the ULRR if judged by the investigator to be related to liver metastases
- serum creatinine ULRR or creatinine clearance greater than or equal to 50 mL/minute (calculated by Cockcroft-Gault formula or measured in a timed urine collection)
- serum calcium below the CTCAE grade 1 upper limit (11.5mg/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 greater than or equal to 1000/mm(3)
- platelet count (Bullet) 100,000/m m(3)
- Prothrombin time (PT) less than or equal to 4 seconds above ULN and partial thromboplastin time (PTT) less than or equal to 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.
- Because the effects of chemotherapy on the developing human fetus are potentially harmful, 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.
Who cannot join
- 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 Investigators 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) due to the poor prognosis of these patients and difficulty ascertaining the cause of neurologic toxicities.
- During Phase II enrollment: Prior therapy with cisplatin. (Cisplatin will be allowed as prior therapy during Phase I enrollment.)
- Women who are currently pregnant or breast-feeding, due to the possible adverse effects on the developing fetus and infant.
- 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 because it will complicate the primary objective of the study. Cancer survivors who have been free of disease for at least two years can be enrolled in this study.
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- 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 greater than or equal to 2 (see Appendix C) 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 interval (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 can not be discontinued for medical reasons, then the patient would not be eligible.
- Congenital long Q wave, T wave (QT) syndrome, or 1st degree relative with unexplained sudden death under 40 years of age.
- Presence of left bundle branch block (LBBB).
- QTc with Bazett's correction that is not measurable, or greater than or equal to 480 msec on screening electrocardiogram (ECG). (Note: If a patient has a QTc interval greater than or equal to 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 (see Appendix C of the protocol) are excluded if QTc is greater than or equal to 460 msec.
- Concurrent medication that may cause QTc prolongation or induce Torsades de Pointes: Those medications in Group One of Appendix C of the protocol will not be allowed. Those medications in Group Two of Appendix C of the protocol will be allowed.
- Crolibulin is a substrate of cytochrome P450 2C8 (CYP2C8), P450 2C9(CYP2C9), P450 2C19 (CYP2C19) and P450 3A4 (CYP3A4). Strong inducers and inhibitors of these enzymes will constitute concomitant medications that are prohibited during the study (See protocol for the complete list). 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).
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Background:
Anaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors; chemotherapy and surgery have had no impact on local control or survival of patients, with a median survival of 3-7 months.
Read more
Crolibulin (EPC2407) is a microtubulin inhibitor that has been shown to have direct antitumor effects in vivo and in vitro, destabilizing spindles and inducing apoptosis, resulting in the disruption of neovascular endothelial cells with disruption of blood flow to the tumor. Early clinical studies with combretastatin, from which crolibulin is derived, demonstrated efficacy in a subset of patients with ATC.
Objectives:
The primary objective in the Phase I portion is to assess the safety and tolerability of cisplatin and crolibulin given in a 21-day cycle in dose-seeking cohorts.
We will assess the toxicities of crolibulin coadministered with cisplatin, evaluate dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) for the combination.
The primary objective in the Phase II portion is to compare the combination crolibulin plus cisplatin versus cisplatin alone in adults with ATC by assessing the duration of progression-free survival (PFS); comparison of the response rates as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) will be an important secondary objective.
We plan on biochemical and immunohistochemical analysis of several tumor parameters including mitotic index, expression of several proteins including epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), BRAF, excision repair cross-complementation group 1 (ERCC1) and tumor protein p53 (TP53). Where sufficient tissue is available we will also perform gene expression analysis, micro ribonucleic acid (microRNA) array analysis, and compare these with 3-deoxy-3 -[(18)F] fluorothymidine (FLT)-positron emission tomography (PET) and tumor growth rate constant.
Eligibility:
Phase I: adults age 18 and older with unresectable, recurrent or metastatic solid tumors.
Phase II: adults age 18 and older with anaplastic thyroid cancer.
In the phase II portion disease must be evaluable by RECIST.
All patients must have adequate hepatic, renal, and bone marrow function.
Design:
The Phase I component consists of dose-escalation cohorts of three to six patients, in which all patients receive both the study drug crolibulin with cisplatin. The MTD and DLT will be determined based on toxicities during the first three weeks of combined therapy.
The Phase II component will be a randomization study, to either crolibulin with cisplatin or cisplatin monotherapy. Patients randomized to cisplatin alone will have the opportunity the opportunity to cross over to the crolibulin arm in the event of tumor progression.
Drug administration will take place on days 1, 2, and 3 for crolibulin, and on day 1 for cisplatin, on a 21-day cycle.
Maximum number of patients for planned enrollment is 70. During the Phase I portion of the study, dose-seeking cohorts of three to six patients will be enrolled until MTD / DLT is reached for a maximum of three dose cohorts [up to 24 patients if one assumes an expansion cohort to twelve patients at the recommended phase 2 (RP2) dose]. During the randomized Phase II trial comparing the activity of the combination of crolibulin plus cisplatin with cisplatin alone it is estimated that a maximum of 40 patients will be enrolled [1:1 randomization 20 + 20 = 40 patients], and we will allow for 6 extra patients to be enrolled to compensate for a small number of non-evaluable patients.
Read the detailed description
Background:
Anaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors; chemotherapy and surgery have had no impact on local control or survival of patients, with a median survival of 3-7 months.
Crolibulin (EPC2407) is a microtubulin inhibitor that has been shown to have direct antitumor effects in vivo and in vitro, destabilizing spindles and inducing apoptosis, resulting in the disruption of neovascular endothelial cells with disruption of blood flow to the tumor.
Objectives:
The primary objective in the Phase I portion is to assess the safety and tolerability of cisplatin and crolibulin given in a 21-day cycle in dose-seeking cohorts.
We will assess the toxicities of crolibulin coadministered with cisplatin, evaluate dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) for the combination.
The primary objective in the Phase II portion is to compare the combination crolibulin plus cisplatin versus cisplatin alone in adults with ATC by assessing the duration of progression-free survival (PFS); comparison of the response rates as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) will be an important secondary objective.
We plan on biochemical and immunohistochemical analysis of several tumor parameters including mitotic index, expression of several proteins including epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), BRAF, ERCC1 and tumor protein p53 (TP53). Where sufficient tissue is available we will also perform gene expression analysis, microRNA array analysis, and compare these with 3-deoxy-3-[(18)F] fluorothymidine (FLT)-positron emission tomography (PET) and tumor growth rate constant.
Eligibility:
Phase I: adults age 18 and older with unresectable, recurrent or metastatic solid tumors.
Phase II: adults age 18 and older with anaplastic thyroid cancer.
In the phase II portion disease must be evaluable by RECIST.
All patients must have adequate hepatic, renal, and bone marrow function.
Design:
The Phase I component consists of dose-escalation cohorts of three to six patients, in which all patients receive both the study drug crolibulin with cisplatin. The MTD and DLT will be determined based on toxicities during the first three weeks of combined therapy. After a minimum of four cycles of concurrent cisplatin and crolibulin, if the patient is achieving clinical benefit in the opinion of the investigator but can no longer tolerate cisplatin, the patient may receive crolibulin alone until he or she experiences unacceptable toxicity or progressive disease.
The Phase II component will be a randomization study, to either crolibulin with cisplatin or cisplatin monotherapy. Patients randomized to cisplatin alone will have the opportunity to cross over to the crolibulin arm in the event of tumor progression. After a minimum of four cycles of concurrent cisplatin and crolibulin, if the patient is achieving clinical benefit in the opinion of the investigator but can no longer tolerate cisplatin, the patient may receive crolibulin alone until he or she experiences unacceptable toxicity or progressive disease.
Drug administration will take place on days 1, 2, and 3 for crolibulin, and on day 1 for cisplatin, on a 21-day cycle.
Maximum number of patients for planned enrollment is 70. During the Phase I portion of the study, dose-seeking cohorts of three to six patients will be enrolled until MTD / DLT is reached for a maximum of three dose cohorts [up to 24 patients if one assumes an expansion cohort to twelve patients at the recommended phase 2 (RP2) dose]. During the randomized Phase II trial comparing the activity of the combination of crolibulin plus cisplatin with cisplatin alone it is estimated that a maximum of 40 patients will be enrolled [1:1 randomization 20 + 20 = 40 patients], and we will allow for 6 extra patients to be enrolled to compensate for a small number of non-evaluable patients.
- Conditions
- Solid Tumor, Anaplastic Thyroid Cancer
- Being tested
- Crolibulin, Cisplatin
- Keywords
- Anaplastic Thyroid Cancer, Crolibulin, Solid Tumors, ATC
- Medical subject headings
- Thyroid Carcinoma, Anaplastic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CrolibulinDrug
Also called EPC2407
Phase I:Dose Level (DL) 1 - 13 mg/m(2) intravenous (IV),DL 2 - 13 mg/m(2) IV, DL 3 - 20 mg/m(2) IV. Phase II: 20 mg/m(2)
CisplatinDrug
Also called CDDP
Phase I:Dose Level (DL) 1- 75 mg/m(2) intravenous (IV),DL 2 - 100 mg/m(2),DL 3 - 100 mg/m(2). Phase II: 100 mg/m(2)
| Study group | Role | What they receive |
|---|---|---|
| Ph I Level -1: Cisplatin + Crolibulin | Experimental | 75mg/m(2) Cisplatin + 8 mg/m(2) Crolibulin Receives: Drug: Crolibulin; Drug: Cisplatin |
| Ph I Level 1: Cisplatin + Crolibulin | Active comparator | 75mg/m(2) Cisplatin + 13 mg/m(2) Crolibulin Receives: Drug: Crolibulin; Drug: Cisplatin |
| Ph I Level 2: Cisplatin + Crolibulin | Active comparator | 100mg/m(2) Cisplatin + 13 mg/m(2) Crolibulin Receives: Drug: Crolibulin; Drug: Cisplatin |
| Ph II Level 3: Cisplatin + Crolibulin | Active comparator | 100mg/m(2) Cisplatin + 20 mg/m(2) Crolibulin Receives: Drug: Crolibulin; Drug: Cisplatin |
| Ph II Level 4: Cisplatin | Active comparator | 100mg/m(2) Cisplatin Receives: Drug: Cisplatin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD) of Cisplatin (Phase I)
MTD is defined as the dose level immediately preceding the dose level at which 2 dose limiting toxicities (DLT) occurred. A DLT is defined as a hematologic or non-hematologic adverse event judged to be possibly, probably, or definitely related to cisplatin per the Common Terminology Criteria in Adverse Events (CTCAE).
Measured: 3 weeks
Maximum Tolerated Dose (MTD) of Crolibulin (Phase I)
MTD is defined as the dose level immediately preceding the dose level at which 2 dose limiting toxicities (DLT) occurred. A DLT is defined as a hematologic or non-hematologic adverse event judged to be possibly, probably, or definitely related to cisplatin per the Common Terminology Criteria in Adverse Events (CTCAE).
Measured: 3 weeks
Progression Free Survival (Phase II)
Progression free survival (PFS) is defined as the duration of time from start of study treatment to time of progression. Response is determined by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as: Complete Response (CR) is disappearance of all target lesions; Partial Response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; and stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
Measured: 6 weeks
Number of Participants With Serious and Non-Serious Adverse Events (Phase I & II)
Here is the number of participants with serious and non-serious adverse events. For a detailed list of adverse events, see the adverse event module.
Measured: 4 years, 6 months and 26 days
Secondary outcomes (2)
Number of Participants Who Underwent Medically-Necessary Interventions
Enrolled participants who had surgical procedures deemed medically necessary for their clinical care.
Measured: 4.5 years
Tumor Growth Rate Constant
Difference in time (days) required for the treated tumors to reach a predetermined target size.
Measured: 21 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Nov 2010 (estimated)
- Study start26 Jan 2011
- Primary completion31 Aug 2015
- Study completion31 Dec 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Solid TumorStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 27 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, James Gulley, M.D., National Institutes of Health Clinical Center (CC)
- Investigators
- James Gulley, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01240590
- Sponsor's protocol ID
- 110027
- Other IDs
- 11-C-0027
- Status last verified
- Feb 2017
- First submitted
- 11 Nov 2010
- Last updated
- 10 Apr 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006 May 10;295(18):2164-7. doi: 10.1001/jama.295.18.2164.
PubMed 16684987Burgess JR, Tucker P. Incidence trends for papillary thyroid carcinoma and their correlation with thyroid surgery and thyroid fine-needle aspirate cytology. Thyroid. 2006 Jan;16(1):47-53. doi: 10.1089/thy.2006.16.47.
PubMed 16487013Truong T, Rougier Y, Dubourdieu D, Guihenneuc-Jouyaux C, Orsi L, Hemon D, Guenel P. Time trends and geographic variations for thyroid cancer in New Caledonia, a very high incidence area (1985-1999). Eur J Cancer Prev. 2007 Feb;16(1):62-70. doi: 10.1097/01.cej.0000236244.32995.e1.
PubMed 17220706Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet. 2016 Dec 3;388(10061):2783-2795. doi: 10.1016/S0140-6736(16)30172-6. Epub 2016 May 27.
PubMed 27240885
Study at a glance
From the registry record, last updated by the sponsor on 10 Apr 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II Trial of Crolibulin (EPC2407) Plus Cisplatin in Adults With Solid Tumors With a Focus on Anaplastic Thyroid Cancer (ATC)
- ClinicalTrials.gov ID
- NCT01240590
- Acronym / sponsor ID
- 110027
- Conditions
- Solid Tumor, Anaplastic Thyroid Cancer
- Keywords
- Anaplastic Thyroid Cancer, Crolibulin, Solid Tumors, ATC
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 27 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 26 Jan 2011 (actual)
- Primary completion
- 31 Aug 2015 (actual)
- Study completion
- 31 Dec 2016 (actual)
- First posted
- 15 Nov 2010 (estimated)
- Results
- Posted 31 Dec 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
Anaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors; chemotherapy and surgery have had no impact on local control or survival of patients, with a median survival of 3-7 months.
Crolibulin (EPC2407) is a microtubulin inhibitor that has been shown to have direct antitumor effects in vivo and in vitro, destabilizing spindles and inducing apoptosis, resulting in the disruption of neovascular endothelial cells with disruption of blood flow to the tumor. Early clinical studies with combretastatin, from which crolibulin is derived, demonstrated efficacy in a subset of patients with ATC.
Objectives:
The primary objective in the Phase I portion is to assess the safety and tolerability of cisplatin and crolibulin given in a 21-day cycle in dose-seeking cohorts.
We will assess the toxicities of crolibulin coadministered with cisplatin, evaluate dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) for the combination.
The primary objective in the Phase II portion is to compare the combination crolibulin plus cisplatin versus cisplatin alone in adults with ATC by assessing the duration of progression-free survival (PFS); comparison of the response rates as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) will be an important secondary objective.
We plan on biochemical and immunohistochemical analysis of several tumor parameters including mitotic index, expression of several proteins including epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), BRAF, excision repair cross-complementation group 1 (ERCC1) and tumor protein p53 (TP53). Where sufficient tissue is available we will also perform gene expression analysis, micro ribonucleic acid (microRNA) array analysis, and compare these with 3-deoxy-3 -[(18)F] fluorothymidine (FLT)-positron emission tomography (PET) and tumor growth rate constant.
Eligibility:
Phase I: adults age 18 and older with unresectable, recurrent or metastatic solid tumors.
Phase II: adults age 18 and older with anaplastic thyroid cancer.
In the phase II portion disease must be evaluable by RECIST.
All patients must have adequate hepatic, renal, and bone marrow function.
Design:
The Phase I component consists of dose-escalation cohorts of three to six patients, in which all patients receive both the study drug crolibulin with cisplatin. The MTD and DLT will be determined based on toxicities during the first three weeks of combined therapy.
The Phase II component will be a randomization study, to either crolibulin with cisplatin or cisplatin monotherapy. Patients randomized to cisplatin alone will have the opportunity the opportunity to cross over to the crolibulin arm in the event of tumor progression.
Drug administration will take place on days 1, 2, and 3 for crolibulin, and on day 1 for cisplatin, on a 21-day cycle.
Maximum number of patients for planned enrollment is 70. During the Phase I portion of the study, dose-seeking cohorts of three to six patients will be enrolled until MTD / DLT is reached for a maximum of three dose cohorts [up to 24 patients if one assumes an expansion cohort to twelve patients at the recommended phase 2 (RP2) dose]. During the randomized Phase II trial comparing the activity of the combination of crolibulin plus cisplatin with cisplatin alone it is estimated that a maximum of 40 patients will be enrolled [1:1 randomization 20 + 20 = 40 patients], and we will allow for 6 extra patients to be enrolled to compensate for a small number of non-evaluable patients.
Detailed description
Background:
Anaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors; chemotherapy and surgery have had no impact on local control or survival of patients, with a median survival of 3-7 months.
Crolibulin (EPC2407) is a microtubulin inhibitor that has been shown to have direct antitumor effects in vivo and in vitro, destabilizing spindles and inducing apoptosis, resulting in the disruption of neovascular endothelial cells with disruption of blood flow to the tumor.
Objectives:
The primary objective in the Phase I portion is to assess the safety and tolerability of cisplatin and crolibulin given in a 21-day cycle in dose-seeking cohorts.
We will assess the toxicities of crolibulin coadministered with cisplatin, evaluate dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) for the combination.
The primary objective in the Phase II portion is to compare the combination crolibulin plus cisplatin versus cisplatin alone in adults with ATC by assessing the duration of progression-free survival (PFS); comparison of the response rates as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) will be an important secondary objective.
We plan on biochemical and immunohistochemical analysis of several tumor parameters including mitotic index, expression of several proteins including epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), BRAF, ERCC1 and tumor protein p53 (TP53). Where sufficient tissue is available we will also perform gene expression analysis, microRNA array analysis, and compare these with 3-deoxy-3-[(18)F] fluorothymidine (FLT)-positron emission tomography (PET) and tumor growth rate constant.
Eligibility:
Phase I: adults age 18 and older with unresectable, recurrent or metastatic solid tumors.
Phase II: adults age 18 and older with anaplastic thyroid cancer.
In the phase II portion disease must be evaluable by RECIST.
All patients must have adequate hepatic, renal, and bone marrow function.
Design:
The Phase I component consists of dose-escalation cohorts of three to six patients, in which all patients receive both the study drug crolibulin with cisplatin. The MTD and DLT will be determined based on toxicities during the first three weeks of combined therapy. After a minimum of four cycles of concurrent cisplatin and crolibulin, if the patient is achieving clinical benefit in the opinion of the investigator but can no longer tolerate cisplatin, the patient may receive crolibulin alone until he or she experiences unacceptable toxicity or progressive disease.
The Phase II component will be a randomization study, to either crolibulin with cisplatin or cisplatin monotherapy. Patients randomized to cisplatin alone will have the opportunity to cross over to the crolibulin arm in the event of tumor progression. After a minimum of four cycles of concurrent cisplatin and crolibulin, if the patient is achieving clinical benefit in the opinion of the investigator but can no longer tolerate cisplatin, the patient may receive crolibulin alone until he or she experiences unacceptable toxicity or progressive disease.
Drug administration will take place on days 1, 2, and 3 for crolibulin, and on day 1 for cisplatin, on a 21-day cycle.
Maximum number of patients for planned enrollment is 70. During the Phase I portion of the study, dose-seeking cohorts of three to six patients will be enrolled until MTD / DLT is reached for a maximum of three dose cohorts [up to 24 patients if one assumes an expansion cohort to twelve patients at the recommended phase 2 (RP2) dose]. During the randomized Phase II trial comparing the activity of the combination of crolibulin plus cisplatin with cisplatin alone it is estimated that a maximum of 40 patients will be enrolled [1:1 randomization 20 + 20 = 40 patients], and we will allow for 6 extra patients to be enrolled to compensate for a small number of non-evaluable patients.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Ph I Level -1: Cisplatin + Crolibulin | Experimental | Drug: Crolibulin, Drug: Cisplatin75mg/m(2) Cisplatin + 8 mg/m(2) Crolibulin |
| Ph I Level 1: Cisplatin + Crolibulin | Active comparator | Drug: Crolibulin, Drug: Cisplatin75mg/m(2) Cisplatin + 13 mg/m(2) Crolibulin |
| Ph I Level 2: Cisplatin + Crolibulin | Active comparator | Drug: Crolibulin, Drug: Cisplatin100mg/m(2) Cisplatin + 13 mg/m(2) Crolibulin |
| Ph II Level 3: Cisplatin + Crolibulin | Active comparator | Drug: Crolibulin, Drug: Cisplatin100mg/m(2) Cisplatin + 20 mg/m(2) Crolibulin |
| Ph II Level 4: Cisplatin | Active comparator | Drug: Cisplatin100mg/m(2) Cisplatin |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- 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 anaplastic thyroid cancer (ATC), including ATC as part of a thyroid carcinoma of another histologic subtype.
- Measurable disease at presentation with disease measurable by Response Evaluation Criteria in Solid Tumors (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.
Key exclusion criteria (20 listed)
- 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 Investigators 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) due to the poor prognosis of these patients and difficulty ascertaining the cause of neurologic toxicities.
- During Phase II enrollment: Prior therapy with cisplatin. (Cisplatin will be allowed as prior therapy during Phase I enrollment.)
- Women who are currently pregnant or breast-feeding, due to the possible adverse effects on the developing fetus and infant.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CrolibulinAlso: EPC2407Phase I:Dose Level (DL) 1 - 13 mg/m(2) intravenous (IV),DL 2 - 13 mg/m(2) IV, DL 3 - 20 mg/m(2) IV. Phase II: 20 mg/m(2) | Drug | Ph I Level -1: Cisplatin + Crolibulin, Ph I Level 1: Cisplatin + Crolibulin, Ph I Level 2: Cisplatin + Crolibulin, Ph II Level 3: Cisplatin + Crolibulin |
| CisplatinAlso: CDDPPhase I:Dose Level (DL) 1- 75 mg/m(2) intravenous (IV),DL 2 - 100 mg/m(2),DL 3 - 100 mg/m(2). Phase II: 100 mg/m(2) | Drug | Ph I Level -1: Cisplatin + Crolibulin, Ph I Level 1: Cisplatin + Crolibulin, Ph I Level 2: Cisplatin + Crolibulin, Ph II Level 3: Cisplatin + Crolibulin, Ph II Level 4: Cisplatin |
Primary outcome
Maximum Tolerated Dose (MTD) of Cisplatin (Phase I)
Time frame: 3 weeks
MTD is defined as the dose level immediately preceding the dose level at which 2 dose limiting toxicities (DLT) occurred. A DLT is defined as a hematologic or non-hematologic adverse event judged to be possibly, probably, or definitely related to cisplatin per the Common Terminology Criteria in Adverse Events (CTCAE).
Maximum Tolerated Dose (MTD) of Crolibulin (Phase I)
Time frame: 3 weeks
MTD is defined as the dose level immediately preceding the dose level at which 2 dose limiting toxicities (DLT) occurred. A DLT is defined as a hematologic or non-hematologic adverse event judged to be possibly, probably, or definitely related to cisplatin per the Common Terminology Criteria in Adverse Events (CTCAE).
Progression Free Survival (Phase II)
Time frame: 6 weeks
Progression free survival (PFS) is defined as the duration of time from start of study treatment to time of progression. Response is determined by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as: Complete Response (CR) is disappearance of all target lesions; Partial Response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; and stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
Number of Participants With Serious and Non-Serious Adverse Events (Phase I & II)
Time frame: 4 years, 6 months and 26 days
Here is the number of participants with serious and non-serious adverse events. For a detailed list of adverse events, see the adverse event module.
2 secondary outcomes
Number of Participants Who Underwent Medically-Necessary Interventions
Time frame: 4.5 years
Tumor Growth Rate Constant
Time frame: 21 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Apr 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 16684987Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006 May 10;295(18):2164-7. doi: 10.1001/jama.295.18.2164.
- Background: PubMed 16487013Burgess JR, Tucker P. Incidence trends for papillary thyroid carcinoma and their correlation with thyroid surgery and thyroid fine-needle aspirate cytology. Thyroid. 2006 Jan;16(1):47-53. doi: 10.1089/thy.2006.16.47.
- Background: PubMed 17220706Truong T, Rougier Y, Dubourdieu D, Guihenneuc-Jouyaux C, Orsi L, Hemon D, Guenel P. Time trends and geographic variations for thyroid cancer in New Caledonia, a very high incidence area (1985-1999). Eur J Cancer Prev. 2007 Feb;16(1):62-70. doi: 10.1097/01.cej.0000236244.32995.e1.
- Derived from this study: PubMed 27240885Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet. 2016 Dec 3;388(10061):2783-2795. doi: 10.1016/S0140-6736(16)30172-6. Epub 2016 May 27.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
James Gulley, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Crolibulin and Cisplatin in people with Solid Tumor and Anaplastic Thyroid Cancer, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 31 Dec 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (MTD) of Cisplatin (Phase I) (time frame: 3 weeks). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01240590, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Apr 2017; AzTrials last refreshed its copy on 7 Nov 2026.