Merkel Cell Carcinoma, Skin Cancer
Conditions
Keywords
Merkel Cell Carcinoma, Skin Cancer
Brief summary
This is an open-label, non-randomized, phase 2 study to assess the feasibility of using cabozantinib in recurrent/metastatic Merkel Cell Carcinoma patients that progressed after platinum-based therapy.
Detailed description
Cabozantinib (XL184) is an inhibitor of multiple receptor tyrosine kinases and was approved by the U.S. Food and Drug Administration (FDA) on 29 November 2012 for the treatment of patients with progressive, metastatic medullary thyroid cancer. It is commercially available as COMETRIQ™ in the United States. During the Pre Treatment Period, participants are consented and qualified (screened) for the study. Treatment will be administered on an outpatient basis. Each treatment cycle lasts 28 days, during which time the participant will be taking the study drug, cabozantinib, once daily. The participant will be given a study drug-dosing diary for each treatment cycle. The diary will also include special instructions for taking the study drug. \- Participants will be followed for 8 weeks after removal from study or until death, whichever occurs first. Participants removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event.
Interventions
DRUGCabozantinib
oral administration
Sponsors
Exelixis
Dana-Farber Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must have histologically or cytologically confirmed Merkel Cell Carcinoma that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective * Must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥10 mm with spiral CT scan (see section 10 for the evaluation of measureable disease). Tumors within a previously irradiated field will be designated as non-target lesions unless progression is documented * Must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin or another organoplatinum compound. Patients are also eligible if they received curative intent platinum-based therapy and progressed within a year of therapy * No prior MET inhibitor is allowed * At least 2 weeks since prior chemotherapy or radiation therapy. At least 3 weeks since prior biologics or investigational agents * Recovery from effects of recent treatment to baseline or CTCAE ≤ grade 1 toxicity from all prior therapies except alopecia and other non-clinically significant AEs * Participants must be ≥18 years of age * ECOG performance status ≤1 * Participants must have normal organ and marrow function * Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation * Ability to understand and the willingness to sign a written informed consent document * Collection of archival tissue specimens for confirmation of Merkel Cell Carcinoma
Exclusion criteria
* Participants who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier * Participants may not be receiving any biologics or investigational agents within 3 weeks * The subject has active brain metastases or epidural disease * History of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib * Has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test ≥ 1.3 the institutional ULN within 7 days before the first dose of study treatment, unless PT/PTT prolongation known to be secondary to conditions not associated with increased bleeding risk (as on antiphospholipid antibody syndrome) * Requires concomitant treatment, in therapeutic doses, with anticoagulants * Active bleeding or pathologic conditions that carry high risk of bleeding * Have experienced clinically significant gastrointestinal bleeding within 6 months before first dose of study treatment * Requires chronic concomitant treatment of strong CYP3A4 inducers * Is unable or unwilling to swallow tablets * Has a corrected QT interval calculated by the Fridericia formula (QTcF)\>500 ms within 28 days before initiation of cabozantinib * Has evidence of tumor invading the GI tract or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib * Has radiographic evidence of cavitating pulmonary lesion(s) * Has uncontrolled, significant intercurrent or recent illness * Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy * History of major surgery within 3 months or minor surgery within 1 month of the first dose of cabozantinib * Pregnant women * Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy * HIV-positive individuals on combination antiretroviral therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 3-Month Disease Control Rate (DCR) | Disease was assessed on day 1 of weeks 3, 5, 7, 9, 11, 13 then every 4 weeks on treatment. Relative to this endpoint was observation up to 3 months on treatment. Length of longest follow up was 83 days. | 3-month DCR is the percentage of participants achieving complete response (CR), partial response (PR) or stable disease (SD) during first 3 months of treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria and lasting at least 3 months from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 3-month Progression-free Survival (PFS) | Assessed every 2 weeks (w) from cycles 3-13 and then every 4w, day 30-37 post-treatment end and up to 8w in long-term follow-up. Length of longest follow up for the KM estimate was 126 days. Relative to this endpoint was 3-month probability. | 3-month PFS is a probability based on the Kaplan-Meier (KM) method. PFS is defined as the duration of time from registration to documented disease progression (PD) or death, or censored at date of last disease assessment. Per RECIST v1.1: PD is at least a 20% increase in the sum of longest diameter (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. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. |
| 3-Month Overall Survival (OS) Rate | 3 months | 3-month OS rate is the percentage of patients alive at 3 months from registration. |
| Grade 3-5 Treatment-Related Adverse Event (AE) Rate | Up to 126 days | All grade 3-5 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Rate is the percentage of treated participants experiencing at least one treatment-related grade 3-5 AE of any type during the time of observation. |
Countries
United States
Participant flow
Recruitment details
Participants enrolled from February 2014 to March 2016.
Participants by arm
| Arm | Count |
|---|---|
| Cabozantinib Cabozantinib 60 mg Oral Daily 28 days (4 weeks) | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Progressive Disease | 4 |
| Overall Study | Unacceptable Toxicity | 2 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Cabozantinib |
|---|---|
| Age, Continuous | 64.9 years STANDARD_DEVIATION 12 |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized White | 6 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 8 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
3-Month Disease Control Rate (DCR)
3-month DCR is the percentage of participants achieving complete response (CR), partial response (PR) or stable disease (SD) during first 3 months of treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria and lasting at least 3 months from baseline.
Time frame: Disease was assessed on day 1 of weeks 3, 5, 7, 9, 11, 13 then every 4 weeks on treatment. Relative to this endpoint was observation up to 3 months on treatment. Length of longest follow up was 83 days.
Population: The analysis population is all enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib | 3-Month Disease Control Rate (DCR) | 12.5 percentage of participants |
Secondary
3-Month Overall Survival (OS) Rate
3-month OS rate is the percentage of patients alive at 3 months from registration.
Time frame: 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib | 3-Month Overall Survival (OS) Rate | 100 percentage of participants |
Secondary
3-month Progression-free Survival (PFS)
3-month PFS is a probability based on the Kaplan-Meier (KM) method. PFS is defined as the duration of time from registration to documented disease progression (PD) or death, or censored at date of last disease assessment. Per RECIST v1.1: PD is at least a 20% increase in the sum of longest diameter (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. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Time frame: Assessed every 2 weeks (w) from cycles 3-13 and then every 4w, day 30-37 post-treatment end and up to 8w in long-term follow-up. Length of longest follow up for the KM estimate was 126 days. Relative to this endpoint was 3-month probability.
Population: The analysis population is all enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib | 3-month Progression-free Survival (PFS) | 0.19 probability |
Secondary
Grade 3-5 Treatment-Related Adverse Event (AE) Rate
All grade 3-5 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Rate is the percentage of treated participants experiencing at least one treatment-related grade 3-5 AE of any type during the time of observation.
Time frame: Up to 126 days
Population: The analysis population is all treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cabozantinib | Grade 3-5 Treatment-Related Adverse Event (AE) Rate | 0 percentage of participants |