Adenocarcinoma of the Prostate
Conditions
Keywords
prostate cancer
Brief summary
This single arm, multicenter, open-label, Phase II study will enroll chemotherapy-naive participants with metastatic, histologically-confirmed adenocarcinoma of the prostate (stage M1 D2). Treatment will continue until there is evidence of disease progression, intolerable toxicity, or other withdrawal criteria are met. Non-surgically castrated participants must continue the use of luteinizing hormone-releasing hormone (LHRH) agonists during protocol treatment.
Detailed description
Thirty-one chemotherapy-naїve participants with asymptomatic metastatic androgen-independent prostate cancer will be enrolled and treated with intravenous (i.v.) IMC-A12 (Cixutumumab) at 10 milligrams per kilogram (mg/kg) administered over 1 hour every 2 weeks. An additional 10 participants will be enrolled and treated with IMC-A12 at a dose of 20 mg/kg every three weeks. Treatment will continue until evidence of disease progression or intolerable toxicity. Radiographic evaluation of response will be performed every 8 weeks for the participants treated with i.v. IMC-A12 at 20 mg/kg.
Interventions
10 mg/kg i.v. infusion over 1 hour every 2 weeks or 20 mg/kg i.v. infusion over 1 hour every 3 weeks.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The participant is male and at least 18 years of age * The participant has histologically-confirmed adenocarcinoma of the prostate * The participant has radiographic evidence of metastatic prostate cancer (stage M1 \[D2\]) * The participant has prostate cancer unresponsive or refractory to hormone therapy * The participant must have evidence of progressive disease defined as at least one of the following: * a. Progressive measurable disease: using conventional solid tumor criteria. * b. Bone scan progression: at least one new lesion on bone scan. * c. Increasing prostate specific antigen (PSA): at least two consecutive rising PSA values over a reference value (PSA #1) taken at least 1 week apart. A third PSA (PSA #3) is required to be greater than PSA #2; if not, a fourth PSA (PSA #4) is required to be greater than PSA #2 * The participant has a PSA ≥ 2 nanograms/milliliter (ng/mL) * The participant has not received prior chemotherapy for metastatic prostate cancer * The participant had prior surgical or medical castration with a serum testosterone level of \< 50 ng/mL. If the method of castration is LHRH agonists, the participant must be willing to continue the use of LHRH agonists during protocol treatment * All clinically significant toxic effects (excluding alopecia) of prior surgery, radiotherapy, or hormonal therapy have resolved to grade ≤ 1 based on National Cancer Institute - Common Terminology Criteria for Adverse Events, (NCI-CTCAE)Version 3.0 * The participant has not received antiandrogen therapy for at least 6 weeks (4 weeks for flutamide) prior to study entry and is without evidence of an antiandrogen withdrawal response. For participants whose progression is documented solely by PSA increase, the most recent PSA value enabling study entry must be drawn after the required antiandrogen washout period * The participant has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 * The participant has adequate organ function including: absolute neutrophil count ≥ 1500/microliter (μL); platelets ≥ 100,000/μL; hemoglobin ≥ 9.0 grams per deciliter (g/dL); bilirubin ≤ 1.5 times the institutional upper limit of normal (ULN); aspartate transaminase (AST) / alanine transaminase (ALT) ≤ 3 times ULN (\< 5x ULN if liver metastases are present); creatinine ≤ 1.5 x ULN (or calculated creatinine clearance \> 60 milliliter/minute (mL/min); and urine protein ≤ 1+ (if urine protein is ≥ 2+, a 24-hour urine collection must demonstrate \< 1000 mg of protein in 24 hours to allow participation in the study) * The participant has fasting serum glucose \< 120 milligrams per deciliter (mg/dL) or below the ULN * The participant has adequate coagulation function as defined by an international normalized ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 1.5 ULN (unless on oral anticoagulant therapy). Participants receiving full-dose anticoagulation therapy are eligible provided they meet all other criteria, are on a stable dose of oral anticoagulant or low molecular weight heparin (and if on warfarin have a therapeutic INR between 2 and 3) * The participant is asymptomatic from prostate cancer. Participants with minimal, infrequent cancer-related symptoms are eligible. Criteria regarding pain and analgesic use are detailed below * The participant has a life expectancy \> 6 months * The participant, if sexually active, agrees to use contraceptives while on study * The participant has provided signed informed consent
Exclusion criteria
* The participant has any active malignancy (other than adequately treated nonmelanomatous skin cancer or other noninvasive or in situ neoplasms), or has an adequately-treated prior cancer but has been disease free for \< 3 years * The participant has an ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia (well-controlled atrial fibrillation is permitted), psychiatric illness/social situations, active bleeding or pathological condition that carries a high risk of bleeding (eg, tumor involving major vessels, tumor invading to rectal lumen, or known varices), or any other serious uncontrolled medical disorder in the opinion of the investigator * The participant has a known hypersensitivity to therapeutic protein products * The participant has known or suspected brain or leptomeningeal metastases * The participant has received radiotherapy ≤ 21 days prior to first dose of IMC-A12 * The participant has received prior radiation therapy to \> 30% of the bone marrow or prior strontium-89, rhenium-186, rhenium-188, or samarium-153 (participants who have received standard dose radiation to the pelvis for prostate cancer and no additional radiotherapy are eligible) * The participant has a known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness * The participant has received more than one course of radiotherapy to a single site of metastatic bony disease * The participant has a bone scan that indicates superscan (that is (ie), extensive metastasis to bone in numerous areas, too numerous to count or define) * The participant is receiving corticosteroids (dexamethasone, prednisone, or others) for anorexia, weight loss, analgesia or other cancer-related symptoms(Corticosteroids may not be instituted once a participant has begun therapy on-study * The participant requires ongoing, regularly scheduled opiate analgesic therapy for cancer related pain. Intermittent, infrequent low-potency opiate-use (example, oxycodone, codeine) is permitted * The participant has a history of prior treatment with other agents that specifically target the insulin-like growth factor (IGF) receptor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Time to Disease Progression (cTTP) for Participants Treated With Cixutumumab | From first dose of study drug until progressive disease (Up to 49.2 months) | cTTP was the time from the first day of treatment to the earliest onset of 1 of the following: tumor progression by Response Evaluation Criteria In Solid Tumors \[RECIST, version 1.0\] criteria: unequivocal evidence of progression by bone scan, new skeletal events, symptomatic progression (for participants without measurable disease), or other clinical events attributable to prostate cancer that in the opinion of the investigator require major interventions. Participants without tumor progression at data cut-off were censored. |
| Area Under the Curve (AUC) of IMC-A12 Administered at a Dose of 20 mg/kg Every 3 Weeks | Up to 42 months (predose, 1, 168, 336 and 504 h postdose for Cycles 1 to 4; additionally 24, 72 or 96 h, 120 and 240 or 246 h postdose for Cycle 4; predose and 1 h post dose for Cycles 5 to 9) | — |
| Maximum Concentration (Cmax) of IMC-A12 Administered at a Dose of 20 mg/kg Every 3 Weeks | Up to 42 months (predose, 1, 168, 336 and 504 h postdose for Cycles 1 to 4; additionally 24, 72 or 96 h, 120 and 240 or 246 h post dose for Cycle 4; predose and 1 h postdose for Cycles 5 to 9) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Prostate Specific Antigen (PSA) Response Rate | From Randomization up to 6.21 months | Percentage of participants with a PSA decrease of at least 50% from baseline PSA provided the participant had a PSA value of at least 2 nanograms per milliliter (ng/ml) at baseline. Percentage calculated as: (number of participants with PSA response rate / total number of participants) \*100. |
| Progression-Free Survival (PFS) Rate at 6 Months | From randomization up to 48.6 months | PFS rate was the proportion of participants who had stable disease (SD), PR, or CR and were alive at 6 months after receiving their first dose of study medication. Response was defined using RECIST v1.0 criteria: CR was defined as the disappearance of all target lesions, PR was defined as at least a 30% decrease in sum of longest diameter of target lesions, and SD was defined as shrinkage or increase in tumor size that did not meet the above criteria. For participants not known to have died as of the data cut-off date and who did not have progressive disease, PFS was censored at the date of last visit with adequate assessment. For participants who received subsequent anticancer therapy prior to disease progression or death, PFS was censored at the date of last visit with adequate assessment prior to the initiation of post-discontinuation anticancer therapy. Percentage of participants = (Number of participants with PFS at 6 months / total number of participants analyzed) \*100. |
| Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs) | From randomization up to 49.2 months (and 30 day follow-up) | Clinically significant events were defined as SAEs and other non-serious adverse events AEs. Participants who died due to progressive disease (PD), AEs while on treatment or died during the 30 day post-treatment are included. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. |
| Maximum Concentration (Cmax) of IMC-A12 Administered at a Dose of 10 mg/kg Every 2 Weeks | Up to 42 months (predose and 1 h postdose for Cycles 1, 5, 9, 13, 17 and 21; additionally immediately following dosing, 168 and 336 h postdose for Cycle 1 only) | — |
| Area Under the Curve (AUC) of IMC-A12 Administered at a Dose of 10 mg/kg Every 2 Weeks | Up to 42 months (predose and 1 h postdose for Cycles 1, 5, 9, 13, 17 and 21; additionally immediately following dosing, 168 and 336 h postdose for Cycle 1 only) | — |
| Time to Radiographically Evident Disease Progression | From first dose of study drug until radiographic progression (up to 48.6 months) | This is the time between first dose and radiographic progression defined as either: progression of measurable or non measurable lesions using the RECIST v 1.0, evidence of progression by bone scan or new skeletal event including new pathologic bone fracture, new bone lesion requiring radiation or surgery, or spinal cord/nerve root compression. Participants without evidence of disease progression at the date of latest tumor or bone radiograph were censored. |
| Number of Participants With Complete Response (CR) or Partial Response (PR) (Tumor Response Rate) | From Randomization up to progressive disease (49.2 months) | Response was defined using RECIST v1.0 criteria: CR was defined as the disappearance of all target lesions and PR was defined as at least a 30% decrease in sum of longest diameter of target lesions |
Countries
United States
Participant flow
Pre-assignment details
Participants who had results for the primary outcome measures were considered to have completed the study. The primary outcome measure is: Composite Time to Disease Progression (cTTP) for Participants Treated With Cixutumumab.
Participants by arm
| Arm | Count |
|---|---|
| Cixutumumab 10 mg/kg Cixutumumab was administered at 10 mg/kg as i.v. infusion over 1 hour every 2 weeks until disease progression or intolerable toxicity. | 31 |
| Cixutumumab 20 mg /kg Cixutumumab was administered at 20 mg/kg as i.v. infusion over 1 hour every 3 weeks until disease progression or intolerable toxicity. | 10 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Cixutumumab 20 mg /kg | Total | Cixutumumab 10 mg/kg |
|---|---|---|---|
| Age, Continuous | 70.2 years STANDARD_DEVIATION 6.78 | 70.1 years STANDARD_DEVIATION 8.64 | 70.0 years STANDARD_DEVIATION 9.26 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 39 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 10 Participants | 40 Participants | 30 Participants |
| Region of Enrollment United States | 10 Participants | 41 Participants | 31 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 41 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / 31 | 10 / 10 |
| serious Total, serious adverse events | 6 / 31 | 0 / 10 |
Outcome results
Primary
Area Under the Curve (AUC) of IMC-A12 Administered at a Dose of 20 mg/kg Every 3 Weeks
Time frame: Up to 42 months (predose, 1, 168, 336 and 504 h postdose for Cycles 1 to 4; additionally 24, 72 or 96 h, 120 and 240 or 246 h postdose for Cycle 4; predose and 1 h post dose for Cycles 5 to 9)
Population: Zero participants were analyzed as the data were not estimable accurately due to the study sampling schedule.
Primary
Composite Time to Disease Progression (cTTP) for Participants Treated With Cixutumumab
cTTP was the time from the first day of treatment to the earliest onset of 1 of the following: tumor progression by Response Evaluation Criteria In Solid Tumors \[RECIST, version 1.0\] criteria: unequivocal evidence of progression by bone scan, new skeletal events, symptomatic progression (for participants without measurable disease), or other clinical events attributable to prostate cancer that in the opinion of the investigator require major interventions. Participants without tumor progression at data cut-off were censored.
Time frame: From first dose of study drug until progressive disease (Up to 49.2 months)
Population: ITT population: All participants who received at least 1 dose of study drug. Participants censored: Cixutumumab 10 mg/kg =7; or Cixutumumab 20 mg/kg = 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cixutumumab 10 mg/kg | Composite Time to Disease Progression (cTTP) for Participants Treated With Cixutumumab | 4.9 months |
| Cixutumumab 20 mg/kg | Composite Time to Disease Progression (cTTP) for Participants Treated With Cixutumumab | 3.2 months |
Primary
Maximum Concentration (Cmax) of IMC-A12 Administered at a Dose of 20 mg/kg Every 3 Weeks
Time frame: Up to 42 months (predose, 1, 168, 336 and 504 h postdose for Cycles 1 to 4; additionally 24, 72 or 96 h, 120 and 240 or 246 h post dose for Cycle 4; predose and 1 h postdose for Cycles 5 to 9)
Population: Participants who received study drug and had evaluable pharmacokinetic (PK) samples for Cmax on Cycle 1 and Cycle 5.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cixutumumab 10 mg/kg | Maximum Concentration (Cmax) of IMC-A12 Administered at a Dose of 20 mg/kg Every 3 Weeks | After first dose | 993 micrograms/milliliter (µg/ml) | Geometric Coefficient of Variation 20 |
| Cixutumumab 10 mg/kg | Maximum Concentration (Cmax) of IMC-A12 Administered at a Dose of 20 mg/kg Every 3 Weeks | After fifth dose | 1780 micrograms/milliliter (µg/ml) | Geometric Coefficient of Variation 53 |
Secondary
Area Under the Curve (AUC) of IMC-A12 Administered at a Dose of 10 mg/kg Every 2 Weeks
Time frame: Up to 42 months (predose and 1 h postdose for Cycles 1, 5, 9, 13, 17 and 21; additionally immediately following dosing, 168 and 336 h postdose for Cycle 1 only)
Population: Zero participants were analyzed as the data were not estimable accurately due to the study sampling schedule.
Secondary
Maximum Concentration (Cmax) of IMC-A12 Administered at a Dose of 10 mg/kg Every 2 Weeks
Time frame: Up to 42 months (predose and 1 h postdose for Cycles 1, 5, 9, 13, 17 and 21; additionally immediately following dosing, 168 and 336 h postdose for Cycle 1 only)
Population: Participants who received study drug and had evaluable PK samples for Cmax on Cycle 1 only in 10 mg/kg group.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cixutumumab 10 mg/kg | Maximum Concentration (Cmax) of IMC-A12 Administered at a Dose of 10 mg/kg Every 2 Weeks | NA µg/ml |
Secondary
Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs)
Clinically significant events were defined as SAEs and other non-serious adverse events AEs. Participants who died due to progressive disease (PD), AEs while on treatment or died during the 30 day post-treatment are included. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
Time frame: From randomization up to 49.2 months (and 30 day follow-up)
Population: Safety population: All participants who received any dose of Cixutumumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cixutumumab 10 mg/kg | Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs) | Deaths due to PD | 1 Participants |
| Cixutumumab 10 mg/kg | Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs) | Non-serious AEs | 28 Participants |
| Cixutumumab 10 mg/kg | Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs) | Deaths due to AEs | 1 Participants |
| Cixutumumab 10 mg/kg | Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs) | SAEs | 6 Participants |
| Cixutumumab 20 mg/kg | Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs) | Deaths due to AEs | 0 Participants |
| Cixutumumab 20 mg/kg | Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs) | Non-serious AEs | 10 Participants |
| Cixutumumab 20 mg/kg | Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs) | Deaths due to PD | 0 Participants |
| Cixutumumab 20 mg/kg | Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs) | SAEs | 0 Participants |
Secondary
Number of Participants With Complete Response (CR) or Partial Response (PR) (Tumor Response Rate)
Response was defined using RECIST v1.0 criteria: CR was defined as the disappearance of all target lesions and PR was defined as at least a 30% decrease in sum of longest diameter of target lesions
Time frame: From Randomization up to progressive disease (49.2 months)
Population: Intent-to-treat (ITT) population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cixutumumab 10 mg/kg | Number of Participants With Complete Response (CR) or Partial Response (PR) (Tumor Response Rate) | 0 Participants |
| Cixutumumab 20 mg/kg | Number of Participants With Complete Response (CR) or Partial Response (PR) (Tumor Response Rate) | 0 Participants |
Secondary
Percentage of Participants With Prostate Specific Antigen (PSA) Response Rate
Percentage of participants with a PSA decrease of at least 50% from baseline PSA provided the participant had a PSA value of at least 2 nanograms per milliliter (ng/ml) at baseline. Percentage calculated as: (number of participants with PSA response rate / total number of participants) \*100.
Time frame: From Randomization up to 6.21 months
Population: Intent-to-treat (ITT) population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cixutumumab 10 mg/kg | Percentage of Participants With Prostate Specific Antigen (PSA) Response Rate | 1.0 Participants |
| Cixutumumab 20 mg/kg | Percentage of Participants With Prostate Specific Antigen (PSA) Response Rate | 0.0 Participants |
Secondary
Progression-Free Survival (PFS) Rate at 6 Months
PFS rate was the proportion of participants who had stable disease (SD), PR, or CR and were alive at 6 months after receiving their first dose of study medication. Response was defined using RECIST v1.0 criteria: CR was defined as the disappearance of all target lesions, PR was defined as at least a 30% decrease in sum of longest diameter of target lesions, and SD was defined as shrinkage or increase in tumor size that did not meet the above criteria. For participants not known to have died as of the data cut-off date and who did not have progressive disease, PFS was censored at the date of last visit with adequate assessment. For participants who received subsequent anticancer therapy prior to disease progression or death, PFS was censored at the date of last visit with adequate assessment prior to the initiation of post-discontinuation anticancer therapy. Percentage of participants = (Number of participants with PFS at 6 months / total number of participants analyzed) \*100.
Time frame: From randomization up to 48.6 months
Population: Intent-to-treat (ITT) population: All participants who received at least 1 dose of study drug. Participants censored: Cixutumumab 10 mg/kg - 7; Cixutumumab 20 mg/kg = 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cixutumumab 10 mg/kg | Progression-Free Survival (PFS) Rate at 6 Months | 41.1 percentage of participants |
| Cixutumumab 20 mg/kg | Progression-Free Survival (PFS) Rate at 6 Months | 40.0 percentage of participants |
Secondary
Time to Radiographically Evident Disease Progression
This is the time between first dose and radiographic progression defined as either: progression of measurable or non measurable lesions using the RECIST v 1.0, evidence of progression by bone scan or new skeletal event including new pathologic bone fracture, new bone lesion requiring radiation or surgery, or spinal cord/nerve root compression. Participants without evidence of disease progression at the date of latest tumor or bone radiograph were censored.
Time frame: From first dose of study drug until radiographic progression (up to 48.6 months)
Population: ITT population: All participants who received at least 1 dose of study drug. Participants censored: Cixutumumab 10 mg/kg = 9; Cixutumumab 20 mg/kg = 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cixutumumab 10 mg/kg | Time to Radiographically Evident Disease Progression | 4.8 months |
| Cixutumumab 20 mg/kg | Time to Radiographically Evident Disease Progression | 3.3 months |