Clinical trial NCT01026623: Cixutumumab and Temsirolimus in Treating Patients With Metastatic Prostate Cancer
Official title: Phase I/II Trial of Anti-IGF-IR Monoclonal Antibody IMC-A12 Plus mTOR Inhibitor Temsirolimus (CCI-779) in Metastatic Castration-Resistant Prostate Cancer (CRPC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hormone-Resistant Prostate Cancer
Prostate Adenocarcinoma
Recurrent Prostate Carcinoma
Stage IV Prostate Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2009-12-04
Enrollment: 16
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I/II trial is studying the side effects of giving cixutumumab together with temsirolimus and to see how well it works in treating patients with metastatic prostate cancer. Monoclonal antibodies, such as cixutumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving cixutumumab together with temsirolimus may kill more tumor cells.

Detailed description: PRIMARY OBJECTIVES:

I. To confirm the safety and tolerability of IMC-A12 (cixutumumab) and temsirolimus using the recommended phase II dose level for advanced solid tumors in chemo-naive patients with metastatic castration-resistant prostate cancer and a rising prostate-specific antigen (PSA). (Phase I) II. To confirm the safety and tolerability of IMC-A12 and temsirolimus given on an every three weeks dosing schedule. (Phase I Extension) II. To determine the tumor response rate and/or composite time to progression (cTTP) for chemotherapy-naive patients with castration-resistant prostate cancer (CRPC) receiving the combination of IMC-A12 and CCI-779 (temsirolimus). (Phase II)

SECONDARY OBJECTIVES:

I. To determine the maximal percent decrease in PSA from baseline. II. To determine the change in PSA doubling time (PSADT). III. To determine the time to PSA progression and 6-month progression-free survival (PFS).

IV. To determine the rate of adverse events.

EXPLORATORY OBJECTIVES:

I. To evaluate changes in circulating tumor cell (CTC) numbers with time. II. To evaluate IGF1R and androgen receptor (AR) in CTCs and correlate with response.

III. To evaluate profiling CTCs at the molecular level by polymerase chain reaction (PCR) for prostate cancer-specific genes.

IV. To explore the association between clinical outcomes, administration of therapy, and serial fludeoxyglucose F 18 (FDG)-positron emission tomography (PET) imaging.

V. To correlate fluorine F 18 FMDHT (18-FDHT)-PET imaging findings with outcome measures of response.

VI. To perform tumor biopsies and evaluate biomarkers that may correlate with active feedback and tumor response to therapy, including anti-insulin receptor substrate 1 (IRS-1), anti-IRS-2, phosphorylated (p) protein kinase B (Akt)(S473), p-ribosomal protein S6 kinase (70/S6K), anti-phospho-AKT1 substrate 1 (proline-rich) (PRAS 40), and phosphatase and tensin homolog gene (PTEN) status.

OUTLINE: This is a multicenter study.

Patients receive cixutumumab intravenously (IV) over 60-70 minutes and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed adenocarcinoma of the prostate

  * Distant metastases evaluable by radionuclide bone scan, CT scan, or magnetic resonance imaging (MRI) within the past 28 days
* Evidence of progressive disease during androgen-deprivation therapy (including a trial of antiandrogen-withdrawal therapy), as defined by ≥ 1 of the following criteria:

  * Progressive measurable disease using conventional solid tumor criteria
  * Bone scan progression, defined as ≥ 2 new lesions on bone scan
  * Increasing PSA, defined as ≥ 2 consecutive rising PSA values over a reference value taken ≥ 1 week apart (the third PSA value must be greater than the second PSA value, if not, a fourth PSA value must be greater than the second PSA value)
* Castrate levels of serum testosterone (i.e., ≤ 50 ng/dL)
* No known brain metastases
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 OR Karnofsky PS 70-100%
* Life expectancy \> 6 months
* Leukocytes ≥ 3,000/μL
* Absolute neutrophil count (ANC) ≥ 1,500/μL
* Platelet count ≥ 100,000/μL
* Hemoglobin ≥ 9 g/dL
* Total bilirubin ≤ 2 times upper limit of normal (ULN)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN
* Serum creatinine ≤ 1.5 times ULN
* Creatinine clearance ≥ 50 mL/min
* Able to adhere to the study visit schedule and other study requirements
* Fertile patients must use effective contraception before, during, and for 3 months after completion of study treatment
* Adequate lung function (pulmonary function test ≥ 70% for diffusion capacity of the lung for carbon monoxide \[DLco\])
* No poorly controlled diabetes mellitus

  * Patients with a history of diabetes are eligible provided their blood glucose is normal (i.e., fasting blood glucose \< 120 mg/dL or \< ULN) and they are on a stable dietary or therapeutic regimen
* No other malignancy within the past 3 years except for treated basal cell or squamous cell carcinoma of the skin or superficial transitional cell carcinoma of the bladder
* No uncontrolled major illness including, but not limited to, any of the following:

  * Active infection, including human immunodeficiency virus (HIV) infection or viral hepatitis
  * Symptomatic congestive heart failure (class III or IV)
  * Unstable angina pectoris
  * Myocardial infarction or acute coronary syndrome within the past year
  * Serious cardiac arrhythmia
  * Significant lung disease
  * Major psychiatric illness
* No other concurrent anticancer agents or treatments
* No prior chemotherapy, except for neoadjuvant chemotherapy
* No prior anti-insulin-like growth factor receptor (IGFR) agents or mammalian target of rapamycin (mTOR) inhibitors
* No prior strontium-89, rhenium-186, rhenium-188, or samarium-153 radionucleotide therapy
* Prior standard-dose radiotherapy to the pelvis for prostate cancer and/or additional external-beam radiotherapy to metastatic sites allowed
* More than 4 weeks since prior surgery, radiotherapy, combined androgen blockade (excluding single-agent gonadotropin releasing-hormone agonists/antagonists), or investigational therapies
* No concurrent second-line hormonal agents, including ketoconazole, diethylstilbestrol, other estrogen-like agents, or finasteride
* No concurrent corticosteroids unless patient is on a stable maintenance dose of hydrocortisone (≤ 30 mg/day) for ≥ 3 months

Primary outcomes:
measure: cTTP
timeFrame: Up to 4 weeks after completion of study treatment
measure: Tumor Response Rate
timeFrame: Up to 4 weeks after completion of study treatment
Secondary outcomes:
measure: Change in PSA Doubling Time
timeFrame: Week 1, Week 5, Week 9, Week 13, Week 17, Week 21 and Week 25
measure: Duration of Effect
timeFrame: From the time of first dose until the time of progression, assessed up to 4 weeks after completion of study treatment
measure: Maximal Percentage Change in Serum PSA as Compared to Week 12 Versus Baseline
timeFrame: From baseline to week 12
measure: Progression-free Survival
timeFrame: From the time of first dose until objective tumor progression or death, assessed up to 4 weeks after completion of study treatment
measure: Rate of Adverse Events According to NCI CTCAE Version 4.0
timeFrame: Up to 4 weeks after completion of study treatment
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Dana Rathkopf
role: PRINCIPAL_INVESTIGATOR
References: