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IMCLONE SYSTEMS   • IMC-A12, NSC-742460

	PRODUCT DESIGNATION
Other Designation	IMC-A12, NSC-742460
Description	IMC-A12 is a fully human IgG1 monoclonal antibody (MAb) that inhibits ligand dependent signaling in tumor cell lines by inhibiting insulin-like growth factor receptor 1 receptor (IGF-1r).

	PRODUCT SOURCE
Primary Developer	ImClone Systems
Affiliations	Dyax   IMC-A12 MAb was isolated by ImClone Systems using an antibody-fragment (Fab) phage display library licensed to the company by Dyax, and then further optimized by ImClone Systems. Also see IMC-1121b record.

	PRODUCT SPECIFICATIONS
Therapeutic Indication	Malignancy
Therapeutic Category	Regulation • Cytostatic
Drug Category	Monoclonal antibody (MAb)
Drug Class	Monoclonal antibody (MAb), human
Technology Details
Mechanism	Signal transduction modulation
Mechanism Details	Insulin like growth factor (IGF) treatment (10 ng/ml ) of serum starved 1483, 183A or TU159 head and neck cell lines resulted in activation of insulin receptor substrate (IRS)-1 and IRS-2, mitogen-activated protein kinase (MAPK) and phosphoinositol-3-kinase (PI3K)/AKT signaling pathways, indicating IGF receptor 1 (IGFr1) overexpression in human head and neck cancer cell lines. A12 pretreatment blocked the activation of all pathways except phosphorylated AKT in a dose-dependent manner. A12 (10 µg/ml) induced G0/G1 cell cycle arrest and blocked cell growth, motility, and anchorage-independent growth. Stimulation of head and neck cancer cells with either IGF or epidermal growth factor (EGF) resulted in receptor heterodimerization and activated phosphorylation of both IGFr1 and EGF receptors (EGFr). Combined treatment with A12 and cetuximab, an EGFr-blocking antibody, reduced cell proliferation, viability and migration more effectively than either agent alone. TU159 tongue cancer cell xenografts grown in athymic nude mice were treated twice weekly for 4 weeks with IP A12 (40 mg/kg), IP cetuximab (40 mg/kg) or both agents (n=8 mice per group; 2 tumors per mouse). While the median tumor volume in untreated control mice increased by 934% during this time, median tumor volumes decreased by 70%, 85%, and 90% in A12, cetuximab, and A12 plus cetuximab treatment groups, respectively. All groups significantly differed in median tumor volume, compared with the control group. Complete regression was seen in 37.5%, 31%, and 47% of tumors treated with A12, cetuximab, and A12 combined with cetuximab, respectivelyy (Barnes CJ, etal, AACR06, LB-247). IGF1r, expressed by various tumor types, provides a critical signaling pathway involved in tumor cell proliferation, migration and survival.
Target	Insulin-like growth factor 1 receptor (IGF1r, IGF-1r, IGFIr, IGF-Ir)
Administration Route	intravenous (IV)
Delivery Details
Toxicities
Diagnostic Tests/Biomarkers	Immunoprecipitation • Western immunoblotting
Diagnostic Test/Biomarker Detail	In a phase I trial (see below) samples are analyzed for serum levels of IGF-I, IGF-II, IGF-BP3, growth hormone, insulin, and C-peptide; trough concentrations and PK sampling; and biomarkers, including IGFIr expression and phosphorylation and insulin receptor expression and phosphorylation via immunoprecipitation and Western immunoblotting. Blood and tumor tissue samples are analyzed for molecular biomarker alterations in the IGF1r-mTOR signaling pathway including, but not limited to, Akt, pAkt, IGF1r, pIGF1r, IRS-1, and PTEN by reverse phase protein arrays, IHC, and ELISA assays. In a phase I/II clinical trial in breast cancer, samples are analyzed for pharmacodynamic assessments. If pre-existing tumor tissue is available, tissue is examined by IHC for markers including pIRS-1, pIGF-Ir, pMAPK, pAkt [S473], pS6, PTEN, and stathmin. FISH is used to assess IGFIr amplification. Gene resequencing is performed to identify mutations of PIK3CA (exons 9 and 20), Akt1, and other genes. Genes IGF-1, IGF-II, IGFBP-1, IGFBP-3, and others are analyzed by RT-PCR.
Cancer Indication	colon cancer • breast cancer • pancreatic cancer • solid tumor • multiple myeloma • sarcoma • prostate cancer • colorectal cancer • head and neck cancer
Preclinical History	The efficacy IMC-A12 in combination with cetuximab and gemcitabine was investigated in mice bearing established BxPC-3, L3.7pL, or MiaPaCa-2 pancreatic xenografts, treated with IMC-A12 , cetuximab, gemcitabine, cetuximab plus gemcitabine, or IMC-A12 plus cetuximab and gemcitabine. The efficacy of IMC-A12 was significant (T/C%=41% and 37%, respectively) in the BxPC-3 and MiaPaCa-2 cell lines but minimal (T/C%=91% in the L3.7pL model. The efficacy of cetuximab plus gemcitabine was significant efficacy in all three models, with a T/C% of 17%, 23%, and 46% for BxPC-3, L3.7pL, and MiaPaCa-2, respectively. Adding IMC-A12 to cetuximab plus gemcitabine therapy significantly increased (p< 0.02) the treatment’s antitumor effects. The 3-agent combination was more active (T/C%=9%, 11%, and 16% for BxPC-3, L3.7pL, and MiaPaCa-2, respectively).than either monotherapy or the cetuximab plus gemcitabine combination. Therefore, this study supports adding IMC-A12 therapy to cetuximab plus gemcitabine to achieve increased antitumor effects in pancreatic cancer (Prewett M, etal, AACR07, Abs. 652). IMC-A12 alone significantly inhibited the growth of the MCF7 breast cancer cell line (IC50=10 nM) and the tamoxifen-resistant breast cancer cell lines MCF-7/LCC2 (MCF7 model selected in tamoxifen) and BT474 (which exhibits tamoxifen resistance due to cross-talk with the overexpressed HEr2 receptor), with 5 nM inducing 20% inhibition, and higher IC50 compared to that with MCF7. Trastuzumab (Herceptin; Genentech) inhibits the growth of BT474 cells (IC50=50 nM), so combinatorial studies were performed. Combination A12 and trastuzumab treatment resulted in additive growth inhibition of BT474 cells, with A12 (5 nM) increasing trastuzumab-dependent growth inhibition by 10%. To model trastuzumab resistance, HEr2-overexpresing SKBR3 cells were cultured in the presence of trastuzumab (10 µg/ml) for 15 weeks. The resulting cell line, SKBR3-HEr10, showed an increased response to A12, with up to 20% growth inhibition, compared to the parent cell line which was unresponsive. This may indicate that a decreased reliance on HEr2 for growth stimulation is compensated by an increased reliance on insulin-like growth factor 1 receptor (IGF-1r) (Best CJM, etal, AACR06, Abs. 1228). In a preclinical study, scientists at Memorial Sloan-Kettering Cancer Center screened 15 human myeloma cell lines and found most of them expressed significant levels of IGF1r. Specific inhibition of IGF1 or serum (which contains IGF)-induced IGF1r signaling was achieved in vitro using a fully human monoclonal anti-IGF1r antibody directed against the human receptor (Imclone, A12). RPMI8226 myeloma cells, with over 80% of cells expressing IGF1r, were established as SC myeloma xenografts in NOD/SCID mice. The A12 antibody was administered IP for 4 weeks. A12 significantly inhibits myeloma cells growth in this model. However, a second SC xenograft myeloma model established with CAG cells, (< 30% of cells expressed IGF1r), showed significantly less tumor suppression with this antibody, indicating that A12 antitumor effect correlates with the level of expression of IGF1r on tumor surface. Immunohistochemistry staining and Tunel assay on tumor tissue recovered from A12-treated RPMI8226-bearing mice showed necrosis rather than apoptosis. A12 treated tumor had significantly decreased vascularization compared to control tumors, as determined by antimouse CD31 and Flk-1 staining. Because VEGF can trigger mouse angiogenesis, VEGF production by the myeloma lines was evaluated using ELISA assay. Most myeloma lines secreted significant amounts of VEGF, and this secretion can be triggered by human IGF1. IGF1r inhibition by A12 in vitro suppressed both constitutive and IGF1-induced secretion of VEGF, indicating a putative anti-angiogenic mechanism associated with IGF1r antibody treatment. A disseminated xenograft myeloma mouse model was established with the MM.1S cell line, transduced with an eGFP/Luciferase fusion gene. The model displayed many features of clinical multiple myeloma in both phenotype (CD38+CD138+ CD45- IGF-IR+ and CD19-CD20-), in vivo engraftment and tissue distribution. Mice were treated with A12, melphalan alone, or a combination of the two agents. At the end of 4 weeks treatment, tumor burden was evaluated by bioluminescence imaging. Tumor burden in A12 or melphalan treatement alone groups decreased about 2 and 4-fold respectively, however, in combination the decrease was up to 30-fold. Mouse OS was prolonged in each treated group, but the combination group had a much more pronounced prolongation of survival, indicating potential usefulness of IGF1r inhibition in enhancing traditional drug antimyeloma activity (Wu K, etal, AACR05, Abs. 5036). IMC-A12 results in a significant reduction of cancer cell proliferation and survival in tumor cell lines.

	CLINICAL STATUS BY INDICATION
Indication	solid tumors, advanced
Latest Status	Phase I (begin 12/05, closed 6/07) USA, phase I (begin 5/08, ongoing 10/08) USA, phase I (begin 5/08, ongoing 10/08) USA
Clinical History	An open label, phase I clinical trial (protocol ID: CDR0000595388, MDA-2007-0595; NCT00678223), was initiated in May 2008, at M.D. Anderson Cancer Center, under Study Chair Aung Naing, MD, to evaluate the safety and efficacy of IMC-A12 in combination with temsirolimus in treating patients with locally advanced or metastatic solid tumors refractory to multiple prior regimens. The trial’s primary objective is to determine MTD, change in phosphorylation levels of Akt and other biomarkers, and tumor metabolism. Secondary objectives are to determine tumor response rate (CR and PR). According to the protocol, during the dose escalation phase, patients are administered temsirolimus (25 mg) IV over 30 minutes and IMC-A12 IV over 60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After MTD is determined, subsequent patients are enrolled into the MTD expansion cohort and assigned to 1 of 3 treatment groups, based on the schedule of administration of the two drugs (sequential or simultaneous). In group A, patients are administered temsirolimus IV over 30 minutes on days 15 and 22 for course 1 and on days 1, 8, 15, and 22 for all subsequent courses, and IMC-A12 (3 mg/kg) IV over 60 minutes on days 1, 8, 15, and 22, about 30 minutes after the infusion of temsirolimus is finished.. In group B, patients are administered IMC-A12 IV over 60 minutes on days 15 and 22 for course 1 and on days 1, 8, 15, and 22 for all subsequent courses, and IV temsirolimus over 30 minutes on days 1, 8, 15, and 22. In group C, patients are administered temsirolimus IV over 30 minutes and IMC-A12 IV over 60 minutes on days 1, 8, 15, and 22. All courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection periodically for pharmacodynamic studies. Patients enrolled in the MTD expansion cohort also undergo tumor biopsy and PET scans periodically. Blood and tumor tissue samples are analyzed for molecular biomarker alterations in the IGF1r-mTOR signaling pathway including, but not limited to, Akt, pAkt, IGF1r, pIGF1r, IRS-1, and PTEN, by reverse phase protein arrays, IHC, and ELISA assays. After completion of treatment, patients are followed within 30 days. The trial is to enroll about 63 patients. In 2007, ImClone completed enrollment of two phase I clinical trials of IMC-A12. In these trials, IMC-A12 was safe with a favorable pharmacokinetic profile, as showed preliminary evidence of antitumor activity as a single agent when administered either weekly or every two weeks. The safety and MTD of IMC-A12 are being evaluated in a phase I clinical trial in advanced, refractory solid tumors, with 15 patients treated so far at 3 (n=7), 6 (n=4), 10 (n=3), and 15 mg/kg (n=1) out of a planned 6 dose levels. Data are available for the first 11 patients. Treatment related toxicities included Grade 1 pruritus, rash, and discolored feces; Grade 2 anemia, psoriasis, hyperglycemia, and an infusion-related reaction; and Grade 3 hyperglycemia. Of the 11 patients, 4 have achieved SD, 2 at the 3 mg/kg dose remained stable for 9+ months (1 male breast cancer, 1 hepatocellular cancer) and 2 at the 6 mg/kg dose (bladder=1 and endometrial=1) were stable after cycle 1. A >25% decline in PSA and stable radiographic disease at time of discontinuation (week 5) for a DLT was observed in a patient with prostate cance. Noncompartmental PK revealed a mean t1/2 of 148 and 209 hours, mean Cmax of 333 and 415 ug/mL, and mean AUC0-Inf of 51,317 and 80,727 hour/ug/ml at the 3 and 6 mg/kg doses. Target trough levels have been achieved. Researchers concluded that weekly administration of IMC-A12 was well tolerated, and MTD has not yet been reached. The PK profile is consistent with that of other monoclonal antibodies (MAb), and there is early evidence of clinical activity (Higano CS, etal, ASCOPC07, Abs. 269, and Higano CS, etal, ASCO07, Abs. 3505). A dose-escalation phase I clinical trial was initiated in the USA to evaluate the safety and MTD of IMC-A12 in patients (n=9) with advanced solid tumors. Patients are eligible if they have histopathologically documented, measurable, advanced primary or recurrent solid tumors that no longer respond to standard therapy or for whom no standard therapy is available, and a life expectancy >3 months. Each cohort consisted of 3-6 patients. IV IMC-A12 was administered weekly for 4 infusions per treatment cycle starting at 3 mg/kg. A total of 6 dose levels up to a maximum of 27 mg/kg are planned. Human anti-human antibodies (HAHA) directed against IMC-A12 are assessed at baseline and before the week 4 dose of each cycle. To date, 9 patients (median age=67 years) have entered thetrial at 2 dose levels. Toxicities related to IMC-A12 include Grade 1 anemia, Grade 1 psoriasis, Grade 1 rash, and Grade 3 hyperglycemia, which was considered a DLT and resulted in patient discontinuation. Out of 9 patients, 2 (1 with breast cancer, 1 with hepatocellular cancer) remain stable after >20 infusions of IMC-A12, and 2 other patients (1 with colon cancer, 1 with prostate cancer) have achieved tumor marker reduction. Non-compartmental PK analysis at the 3 mg/kg dose level revealed mean t1/2=111.3 hours, mean Cmax=192 µg/mL, and mean AUC from 0 to infinity=22266 hr*µg/mL. Target trough levels determined from preclinical xenograft studies have been achieved. Weekly administration of IMC-A12 is well tolerated in this patient population, with early evidence of clinical activity. PK profile is consistent with that of other monoclonal antibodies. Dose escalation continues (Higano C, etal, EORTC-NCI-AACR06, Abs. 648). ImClone expects to complete this phase I clinical trial in the first half of 2007. Following successful filing of an IND for IMC-A12 in 2005, a phase I clinical trial (protocol ID: CP13-0501) with this agent was initiated in in the USA, in December 2005, in patients with advanced solid tumors. Participating sites include the Seattle Cancer Care Alliance (Seattle, WA), under PI Celestia Higano, MD, Premiere Oncology of Arizona (Scottsdale, AZ), Karmanos Cancer Institute (Detroit, MI) and Vanderbilt-Ingram Cancer Center (protocol ID: VICCPHI0541), under PI Mace Rothenberg, MD.
Indication	prostate cancer, androgen-independent, metastatic, first line • prostate cancer, androgen-independent, metastatic, second line
Latest Status	Phase II (begin 8/07, completed 8/08) USA, phase II (begin 5/08, ongoing 10/08) USA
Clinical History	A multicenter (n=14), randomized, open label, phase II clinical trial (protocol ID: CP18-0601; NCT00683475), was initiated in May 2008, in the USA, to evaluate the safety and efficacy of IMC-A12 or IMC-1121B in combination with mitoxantrone and prednisone in treating patients with metastatic, androgen-independent prostate cancer following disease progression on docetaxel-based chemotherapy. The trial’s primary objective is to determine a composite PFS. Secondary objectives are to assess safety and tolerability, determine TTP, PSA response rate, composite PFS rates, OS, ORR, and CR. According to protocol, patients in arm 1 are administered IMC-A12 in combination with mitoxantrone and prednisone. One cycle is equal to 3 weeks or 21 days. Patients are administered mitoxantrone (12 mg/m²)) on day 1. On days 1, 8, and 15, patients are administered IV IMC-A12 (6 mg/kg). Patients are also administered PO prednisone (5 mg) twice daily. In arm 2, patients are administered IMC-1121B in combination with mitoxantrone (12 mg/m²)) on day 1 and PO prednisone (5 mg) daily. Patients are also administered IV IMC-1121B (6 mg/kg) on days 1, 8, and 15. In both arms, patients continue treatment until disease progression, intolerable toxicity, or other withdrawal criteria. Mitoxantrone is to be administered for up to 12 cycles (total cumulative dose of mitoxantrone is restricted to = 144 mg/m2), or until there is evidence of disease progression, intolerable toxicity, or other withdrawal criteria. The trial is to enroll about 132 patients. In August 2007, patient enrollment was initiated in a multicenter, nonrandomized, open label, active control, single arm, phase II clinical trial (protocol ID: CP13-0603; NCT00520481) of IMC-A12 in advanced prostate cancer. The trial will enroll up to 30 patients with metastatic, histologically confirmed adenocarcinoma of the prostate (Stage M1 D2) who have not previously been treated with chemotherapy. Treatment will continue until there evidence of disease progression, intolerable toxicity, or other withdrawal criteria. Patients not castrated surgically will continue the use of LHRH agonists during protocol treatment. Primary objective is TTP in patients treated with IMC-A12 every 2 weeks. Secondary outcomes include safety and tolerability, time to radiographically evident disease progression, ORR for all patients and the subset of patients with measurable disease, and PSA response rate. One of the participating centers is Seattle Cancer Care Alliance, under PI Celestia Higano, MD (tel: 206-288-1189). This trial was completed as of August 2008.
Indication	colorectal cancer, metastatic, refractory
Latest Status	Phase II (begin 6/07, ongoing 10/08) USA
Clinical History	A multicenter (n=4), randomized, open label, phase II clinical trial (protocol ID: CP13-0605; NCT00503685), was initiated in June 2007, in the USA, to evaluate the efficacy of IMC-A12 as a single agent or in combination with cetuximab (Erbitux; ImClone Systems) in patients with metastatic colorectal cancer that progressed on at least one prior anti-EGFr therapy. According to protocol, patients in arm 1 are treated with single agent IMC-A12 (10 mg/kg) IV over 1 hour, every 2 weeks, until progressive disease, unacceptable toxicity, or withdrawal consent. In arm 2, patients are treated with cetuximab (500 mg/m²) IV over 2 hours, followed by a 1-hour observation period, then IMC-A12 (10 mg/kg) administered IV over 1 hour (both treatments are administered every 2 weeks). PK and pharmacodynamic assessments qre performed using samples from the first 10 patients enrolled in each arm at Memorial Sloan Kettering Cancer Center (20 patients total). The trial’s primary objective is to assess objective response rate (ORR) by RECIST guidelines re-evaluated every 6 weeks. Participating centers include UCLA Medical Center, under PI J. Randolph Hecht, MD; Yale Comprehensive Cancer Center, under PI M. Wasif Saif, MD, Memorial Sloan-Kettering Cancer Center, under PI Leonard B. Saltz, MD; and Roswell Park Cancer Institute, under PI Marwan Fakih, MD. The trial is expected to enroll 75 patients.
Indication	solid tumors, pediatric, relapsed or refractory
Latest Status	Phase I (begin 1/08, ongoing 10/08) USA
Clinical History	A multicenter, phase I clinical trial (protocol ID: CDR0000585700, COG-ADVL0712; NCT00609141), under IND #100947, was initiated in January 2008 in the USA by the Children's Oncology Group (COG) with IMC-A12 in treating young patients (<21 years of age) with relapsed or refractory Ewing sarcoma/peripheral primitive neuroectodermal tumors or other solid tumors. Primary outcome measures are MTD or recommended phase II dose, toxicity profile, response rate (CR and PR), and PK. To preliminarily define the antitumor activity of this drug in children with relapsed or refractory solid tumors within the confines of a phase I study. Secondary objectives are to obtain initial phase II efficacy data; examine change in IGF-Ir and insulin receptor (Ir) levels and IGF-Ir and Ir activation in lymphocytes as biomarkers of IMC-A12 action and specificity; evaluate the effect of this drug on circulating levels of proteins involved in linear growth and glucose homeostasis, including IGF-I, IGF-II, IGF-BP3, growth hormone, insulin, and C-peptide; and develop exploratory data concerning biomarkers of activity. According to the protocol, patients are stratified according to disease in stratum 1 inclusing refractory solid tumors versus stratum 2 comprising patients with Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET). Accrual to stratum 2 is restricted to patients >/=12 years of age until safety is determined in stratum 1; then accrual will continue for patients of all ages. Patients are treated with IMC-A12 IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 4 weeks for up to 2 years in the absence of unacceptable toxicity or disease progression. Patients undergo blood sample collection periodically for PK, immunogenicity, and other correlative studies. Tumor tissue samples from patients with Ewing sarcoma/peripheral PNET are banked for future research. After completion of study treatment, patients are followed at 30 days. Approximately 48 patients are to enroll in this trial. Participating institutions include Children's National Medical Center (Washington, DC), and Oregon Health and Science University (OHSU) Cancer Institute (Portland, OR). Study Chair is Suman Malempati, MD, Doernbecher Children's Hospital at OHSU.
Indication	head and neck cancer, metastatic, recurrent or refractory
Latest Status	Phase II (begin 1/08, ongoing 10/08) USA
Clinical History	A multicenter (n=3), randomized, open label phase II clinical trial (protocol ID: CP13-0706; NCT00617734) was initiated in January 2008 in the USA, with IMC-A12 monotherapy or in combination with cetuximab, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (oropharynx, hypopharynx, or larynx) that progressed on previous platinum-based chemotherapy with or without radiation therapy. According to the protocol, patients in arm 1 are treated with a IMC-A12 (10 mg/kg) over 1 hour every 2 weeks. In arm 2, patients are treated with IMC-A12 (10 mg/kg) followed in an hour by cetuximab (500 mg/m²), administered IV over 2 hours. A cycle is defined by 4 weeks of therapy. Patients continue treatment until progressive disease or unacceptable toxicity. The trial’s primary objective is PFS. Secondary objectives include 6-month PFS rate, OS rate, duration of response, safety and tolerability and AE profile. An estimated 90 patients are to enroll in this trial to be completed in June 2009. Participating institutions include M. D. Anderson Cancer Center (Orlando, FL), under PI Jennifer Tseng, MD, University of Chicago, under PI Ezra Cohen, MD, Thoracic Head and Neck Medical Oncology (Houston, TX) under PI Bonnie Glisson, MD.
Indication	soft-tissue sarcoma, advanced or metastatic, refractory
Latest Status	Phase II (begin 7/08) USA
Clinical History	A multinational, 5-tier, open label phase II clinical trial (protocol ID: CP13-0707; NCT00668148) was initiated in July 2008, at M. D. Anderson Cancer Center (Orlando, FL), under PI Gregory K Pennock, MD, to evaluate the efficacy of IMC-A12 in adult and adolescent patients with several types of previously treated, advanced or metastatic soft-tissue sarcoma, selected based on the potential relevance of IGF-1r to tumor growth. Up to 185 patients are to be enrolled with various types of soft-tissue sarcoma including Ewing's sarcoma, peripheral neuroectodermal tumors (PNET), rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, and synovial sarcoma. According to the protocol IMC-A12 (10 mg/kg) is administered IV over 1 hour every 2 weeks. A treatment cycle will be defined as 6 weeks, with radiological evaluation every cycle. The Simon two-stage design is applied separately to each tier; safety and response in the initial 17 patients in each tier will be used to determine whether to extend enrollment to the target total of 37 patients per tier. The primary objective of this trial is PFS. Secondary objectives are to evaluate the objective response rate, safety, tolerability, and AE profile of IMC-A12; determine the time to onset, duration of response, OS, clinical benefit rate; and assess the development of antibodies against IMC-A12. The rationale for the trial is based on supportive preclinical and biologic findings indicating that the IGF-1r and related signaling pathways may be overstimulated in these tumor types, and therefore particularly sensitive to IMC-A12.
Indication	breast cancer, locally recurrent or metastatic, second line • breast cancer, locally advanced or metastatic, HEr2-positive, refractory
Latest Status	Phase I/II (begin 2/08, ongoing 10/08) USA (combination), phase I/II (begin 1/08, ongoing 10/08) USA (combination)
Clinical History	An open label, phase I/II clinical trial (protocol ID: CDR0000598057, MAYO-MC0736; NCT00699491), was initiated in February 2008, at the Siteman Cancer Center at Barnes-Jewish Hospital (St. Louis, MO), under Study Chair Cynthia X. Ma, MD, PhD, to evaluate the safety and efficacy of IMC-A12 in combination with temsirolimus in treating patients with locally recurrent or metastatic breast cancer. The trial’s primary objectives are to determine the recommended dose level, safety profile, and antitumor activity, previously treated with at least one but not more than 2 regimens. Secondary objectives are to determine the adverse events, duration of response, PFS, survival time, serum estradiol and progesterone levels prior to treatment, and levels of IGF-1, IGF-2, and IGFBP1-3, insulin, glucose, and C-peptide. According to protocol, patients are administered temsirolimus IV over 30 minutes and IMC-A12 IV over 60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Peripheral blood samples are collected periodically for circulating markers and mononuclear cells. Samples are analyzed for pharmacodynamic assessments. If pre-existing tumor tissue is available, tissue is examined by IHC for markers including pIRS-1, pIGF-Ir, pMAPK, pAkt [S473], pS6, PTEN, and stathmin. FISH is used to assess IGFIr amplification. Gene resequencing is performed to identify mutations of PIK3CA (exons 9 and 20), Akt1, and other genes. Genes IGF-1, IGF-II, IGFBP-1, IGFBP-3, and others are analyzed by RT-PCR. After completion of treatment, patients are followed periodically for up to 2 (phase I) or 5 (phase II) years. The trial, to enroll about 68 patients. A multicenter (n=62), randomized, phase II clinical trial (protocol ID: CDR0000596070, NCCTG-N0733; NCT00684983), was initiated by SWOG, in January 2008, in the USA, to evaluate the safety and efficacy of capecitabine in combination with lapatinib with or without IMC-A12, in treating patients with Stage III/IV, HEr2-positive breast cancer previously treated with trastuzumab and an anthracycline or taxane. The trial’s primary objective is PFS. Secondary objectives are to determine OS, time-to-treatment failure, confirmed tumor response rate, duration of response, AE profile, QoL, and various tumor tissue and circulating tumor-cell biomarkers. According to the protocol, in arm 1, patients are administered oral capecitabine twice daily on days 1-14 and oral lapatinib ditosylate once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. In arm 2, patients are administered capecitabine and lapatinib ditosylate as in arm I, and IV IMC-A12 IV over 1 hour on days 1, 8, and 15. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. The trial, to enroll about 154 patients, is being conducted under Study Chairs Paul Haluska, MD, PhD, Mayo Clinic (Rochester, MN) and Hannah M. Linden, MD, Seattle Cancer Care Alliance (Seattle, WA).
Indication	hepatocellular carcinoma (HCC), locally advanced or metastatic, inoperable
Latest Status	Phase II (begin 3/08, ongoing 10/08) USA
Clinical History	An open label, phase II clinical trial (protocol ID: CDR0000589633, MSKCC-08015; NCT00639509), was initiated in March 2008, at Memorial Sloan-Kettering Cancer Center, under Study Chair Ghassan Abou-Alfa, MD, to evaluate the safety and efficacy of IMC-A12 in inoperable, locally advanced, metastatic hepatocellular carcinoma, not previously treated with systemic chemotherapy except for sorafenib tosylate. The trial’s primary objective is to determine PFS at 4 months and best overall response rate. Secondary objectives are to determine the OS and MST, safety, tolerability, and AE profile; elucidate the differences in PFS of patients who are hepatitis B positive/hepatitis C negative versus patients who are hepatitis B negative/hepatitis C positive; and evaluate the ability of the volumetric method to assess response. According to the protocol, patients are administered IMC-A12 IV over 1 hour once weekly. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo serum sample collection at baseline for future tissue-based correlative studies. Previously collected paraffin embedded tumor tissue samples are also stored for future correlative studies. After completion of treatment, patients are followed every 3 months for at least 1 year. The trial is to enroll about 50 patients.
Indication	pancreatic cancer, metastatic, first line
Latest Status	Phase I/II (begin 3/08, ongoing 10/08) USA
Clinical History	A multicenter (n=10), randomized, phase I/II clinical trial (protocol ID: CDR0000586427, SWOG-S0727; NCT00617708), was initiated in March 2008, in the USA, to evaluate the safety and efficacy of IMC-A12 in combination with gemcitabine and erlotinib versus gemcitabine plus erlotinib as first line treatment in patients with metastatic pancreatic cancer. The trial’s primary objectives are to determine the recommended phase II dose and PFS. A secondary objective is to determine OS. In arm 1, patients are administered oral erlotinib once daily on days 1 to 28, IV gemcitabine IV over 30 minutes on days 1, 8, and 15, and IV IMC-A12 over 60 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. In arm 2, patients are administered erlotinib and gemcitabine as in arm I. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of treatment, patients are followed every 6 months for up to 3 years. The trial, to enroll about 118 patients, is being conducted under Study Chair Robert P. Whitehead, MD, University of Texas (Houston, TX).
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