Indication

solid tumors, advanced • lymphoma, advanced

Latest Status

Phase I (begin 1/05, ongoing 1/06) Europe (Spain), phase I (begin 5/06, terminated 10/08) USA

Clinical History

In a phase I clinical trial of PM00104 in patients with advanced solid tumors or lymphoma, sequential cohorts of 3-6 patients were administered IV PM00104 in doses of 0.225 (n=3), 0.45 (n=3), 0.9 (n=3), 1.8 (n=3), 3.0 (n=9), and 3.6 mg/m² (n=6) every 3 weeks. Participating sites include Royal Marsden Hospital (Sutton, UK) and Hospital Universitario 12 de Octubre (Madrid, Spain). A total of 27 patients (median age=58 years, ECOG PS 0/1/2=14/11/2) were treated. Of 6 patients at the 3.6 mg/m² dose, 2 experienced DLT, defining the MTD. A patient with colorectal cancer with extensive liver metastases developed Grade 4 thrombocytopenia and neutropenia, Grade 3 transaminase elevation, and Grade 4 troponin I elevation without cardiac symptoms or ECG alterations; all toxicities are resolved. Another patient with adrenal carcinoma developed Grade 3 nausea, vomiting and Grade 3 asthenia despite antiemetics, which resolved with dexamethasone 2 days after infusion. Hematologic >/= Grade 3 AE include Grade 3 leukopenia (3.0 mg/m²=2), Grade 4 leukopenia (3.6 mg/m²=1), Grade 4 neutropenia (0.225 mg/m²=1, 3.0 mg/m²=1, 3.6 mg/m²=1), Grade 3 neutropenia (3.0 mg/m²=3), Grade 4 thrombocytopenia (3.6 mg/m²=1), and Grade 3 anemia (1.8 mg/m²=1). Biochemical abnormalities were increased ALT (Grade 1=5, Grade 2=2, Grade 3=1), increased AST (Grade 1=8, Grade 3=2), amylase abnormalities (Grade 1=2, Grade 2=1), increased CPK (Grade 1=2), increased creatinine (Grade 1=10, Grade 2=1), and increased total bilirubin (Grade 1=2, Grade 2=2, Grade 3=1). AE (both drug-related and non-drug-related) include anorexia (Grade 1/2=3, Grade 3=1), diarrhea (Grade 1/2=2, Grade 3=1), asthenia (Grade 1/2=9, Grade 3=4), injection site reaction (Grade 1/2=5), nausea (Grade 1/2=15, Grade 3=1), vomiting (Grade 1/2=10, Grade 3=1), and increased transaminases (Grade 3=1). Cardiac events were observed at the 3.6 mg/m² dose and included 2 patients with Grade 4 increase in cardiac troponin I, both without cardiac symptoms or relevant ECG or ECHO alterations, and another patient with asymptomatic T-wave inversion with no alterations in serum cardiac markers, with normal ECHO and coronary angiography. Median LVEF change was -2, and there was no decrease below the normal range in any patient. Disease stabilized in 9 patients and progressed in 17 patients. No DLT was observed in the patients from the 3.0 mg/m² cohort, establishing this dose as the recommended dose (RD). To date, disease stabilized > 3 months in 4 patients (0.9 mg/m²=1, 3.0 mg/m²=3). PK data at the RD cohort indicate that drug AUC and Cmax increase proportionally across the dose range up to 3.0 mg/m². A higher than proportional increase in Cmax and AUC is suggested with higher doses. PM00104 has a long half-life (up to 50 hours), wide volume of distribution (median of 890 l), and median clearance of 44 l/hour. Preliminary compartmental analysis showed that data were best fitted to a three-compartment model (Gallerani E, etal, ASCO07, Abs. 2517).

A multicenter, open label, dose-escalation phase I clinical trial (protocol ID: PM104-A-002-05 NCT00359294) was initiated in May 2006 with PM00104 in patients with refractory advanced solid tumors or lymphoma. Primary outcome measures are safety, tolerability, DLT and MTD of PM00104. Secondary objectives are to determine preliminary PK, evaluate relationship between PK/pharmacodynamics and evaluate preliminary antitumor activity of PM00104. Dose-escalation guidelines follow an accelerated phase I design for conventional cytotoxic agents in order to minimize the number of patients treated at sub-toxic dose levels. According to the protocol, PM00104 is administered IV over 1 hour daily for 5 days, every 3 weeks. A total of 35 patients are to enroll in this trial. Participating institutions include Fox Chase Cancer Center, under PI Nancy Lewis, MD. This trial was terminated in October 2008 because it was not considered not necessary to continue with this trial since the recommended phase II dose was reached in other phase I trials.

In January 2005, a dose-escalation, open label, multicenter phase I clinical trial was initiated with Zalypsis, in Spain, in patients with advanced solid tumors or lymphoma. Zalypsis is administered as a 1 hour IV infusion every 3 weeks.

Current as of

April 23, 2010

Indication

healthy volunteers

Latest Status

Phase I (begin 7/06, completed 9/06) USA, phase I (begin 12/07, completed 4/09) USA, phase I (begin 5/08, completed 1/09) USA, phase I (begin 10/08, completed 2/09) USA, phase I (planned 12/08, ongoing 11/09) Europe (Russia), phase I (begin 5/09, completed 6/09) USA, phase I (begin 4/09, completed 4/09) USA, phase I (begin 2/09, completed 4/09) USA

Clinical History

A randomized, open label, phase I clinical trial (protocol ID: 3144A2-1112; NCT00932464) was planned as of March 2010, to evaluate the effect of a high-fat meal on the relative bioavailability and PK of single dose neratinib in healthy patients. The trial’s primary objective is to assess PK. According to the protocol, patients are administered a single dose of neratinib (240 mg). The trial is to enroll about 24 patients.

A nonrandomized, open label, phase I clinical trial (protocol ID: 3144A1-1110; NCT00864487) was initiated in May 2009, in the USA, to determine the effect of rifampin on the PK of neratinib in healthy volunteers. The trial’s primary outcome measure is to determine the PK. This trial is to enroll about 24 volunteers and was completed in June 2009.

A nonrandomized, open label, crossover assignment, phase I clinical trial (protocol ID: 3144A1-1119; NCT00860223) was initiated in April 2009, in the USA, to evaluate the potential effect of multiple doses of neratinib on the PK of digoxin in healthy volunteers. The trial’s primary outcome measure is to determine the PK parameters from the concentration of digoxin in blood and urine. This trial is to enroll about 24 volunteers and was completed in April 2009.

A randomized, open label, phase I clinical trial (protocol ID: 3144A1-1117; NCT00814060) was initiated in February 2009, in the USA, to examine the bioavailability of two tablet formulations of neratinib compared to a capsule formulation in healthy volunteers. The trial’s primary outcome measure is to collect blood samples to determine the PK of the various formulations of neratinib. According to the protocol, volunteers are administered a neratinib tablet (40 or 240 mg) or a neratinib capsule (80 mg). This trial is to enroll about 24 volunteers and was completed in April 2009.

A nonrandomized, open label, phase I clinical trial (protocol ID: 3144A1-1111; NCT00781430) was initiated in December 2008, in Europe (Russia), to evaluate the PK of HKI-272 in treating patients with chronic hepatic impairment and in matched healthy volunteers. Participants must be nonsmokers or smoke fewer than 10 cigarettes per day, must not have family history of QT prolongation, syncope, seizure, or unexplained cardiac-related death, and must not have history of any disorder that may prevent the successful completion of the trial. The trial’s primary objectives are to assess the PK, safety and tolerability of HKI-272. The trial is to enroll about 27 participants.

A 2-center, randomized, double blind, parallel assignment, phase I clinical trial (protocol ID: 3144A1-1116; NCT00757809) was initiated in October 2008, in the USA, to evaluate the safety of HKI-272 in healthy volunteers. The trial’s primary objective is to investigate the occurrence of diarrhea. According to the protocol, volunteers are administered HKI-272 (240 mg) once daily or (120 mg) twice daily for 14 days. This trial is to enroll about 50 volunteers and was completed in February 2009.

A randomized, double blind, crossover assignment, phase I clinical trial (protocol ID: 3144A1-105; NCT00708903) was initiated May 2008, in the USA, to determine whether HKI-272 affects the rhythms of the heart (cardiac repolarization) in healthy adult volunteers. The trial’s primary objective is to assess QTc interval. According to the protocol, volunteers are administered HKI-272, moxifloxacin, or placebo. The trial is to enroll about 60 volunteers and was completed in January 2009.

A nonrandomized, open label, phase I clinical trial (protocol ID: 3144A1-1108; NCT00550212) was initiated in December 2007, in the USA, to evaluate the PK, mass balance, and metabolic distribution of single dose HKI-272 in healthy male volunteers. The trial’s primary objective is to evaluate the mass balance and metabolic distribution of C14-labeled HKI-272. According to the protocol, volunteers are administered HKI-272 (240 mg) as a single dose capsule and solution. The trial is to enroll about 6 volunteers and was completed in April 2009.

A randomized, double blind, placebo-controlled, phase I clinical trial (protocol ID: 3144A1-107; NCT00366600) was initiated in July 2006, in the USA, to evaluating the safety, tolerability, and PK of PO HKI-272 in healthy volunteers. This trial was completed in September 2006.

Indication

solid tumors, HEr2-positive, refractory

Latest Status

Phase I (begin 11/03, completed 12/07) USA; phase I/II (begin 4/08, ongoing 4/10) USA, Europe (Belgium, France, Netherlands, Poland, Spain), Hong Kong

Clinical History

In the open label, 2-part, phase I/II clinical trial (protocol ID: 3144A1-2204; NCT00706030) evaluating the safety and efficacy of neratinib in combination with vinorelbine in patients with solid tumors and HEr2+ metastatic breast cancer, in part 1, patients with solid tumors were treated with ascending oral doses of neratinib (160 mg or 240 mg) and IV vinorelbine (25 mg/m²) on days 1 and 8 every 3 weeks, to determine the MTD. Part 2 is assessing the clinical activity, safety, and PK of this combination in adults with HEr2+ metastatic breast cancer previously treated with >2 prior chemotherapy-containing regimens and trastuzumab for >/=6 weeks, with or without prior lapatinib exposure. The primary endpoint is objective response rate. Tumor responses are assessed by modified RECIST every 6 weeks. In part 1 (n=12), no DLT were observed with neratinib (240 mg) and vinorelbine (25 mg/m²), which was determined to be the MTD. In part 2, as of 19 Oct 2009, 34 patients with HEr2+ metastatic breast cancer were enrolled and treated at the MTD (prior lapatinib=6; no prior lapatinib=28). The median duration of neratinib treatment was 11.9 weeks (range=0.1-47.0). In part 2, the most common treatment-emergent AE (all grades) included diarrhea (prior lapatinib, 100%; no prior lapatinib, 93%), vomiting (50% and 21%), nausea (33% and 46%), neutropenia (50% and 39%), and fatigue (33% and 29%). AE leading to dose reductions included neutropenia (n=4), diarrhea (n=2), vomiting, gastroenteritis, increased alanine aminotransferase, and starvation (n=1 for each). One patient withdrew because of diarrhea. Preliminary PK data suggest no apparent interaction between the two drugs. Among 18 patients from part 2 evaluable for efficacy, including 4 with and 14 without prior lapatinib therapy; objective response rates (based on investigator-assessed radiographic and clinical data) were 25% and 43%, respectively. According to preliminary data from this trial, the combination of neratinib and vinorelbine is tolerable with promising antitumor activity in patients in this setting (Awada A, etal, IMPAKT10, Abs. 145P).

In the first part of the 2-part phase I/II clincial trial (protocol ID: 3144A1-2204; NCT00706030), ascending daily doses of neratinib (160 mg, or 240 mg) were combined with IV vinorelbine (25 mg/m²) administered on days 1, 8 every 3 wks. Tumor measurements were taken every 6 weeks based on modified RECIST criteria. Altogether, 12 patients were enrolled with 6 treated at each dose level. As of October 30, 2008, according to data from 12 patients (5 patients are still on trial), the median duration of treatment was 1.9 (range=1.5-2.7) months. There was only 1 DLT of Grade 3 neuropathy in a patient with preexisting Grade 1 neuropathy) at 160 mg neratinib, so the dose was escalated to 240 mg neratinib. In this cohort, there were no DLT, and because the neratinib and vinorelbine doses reached full standard doses there was no need for further dose escalation. AE of any cause, and any grade in >/=15% of patients included diarrhea (92%), nausea (67%), constipation (50%), fatigue (42%), vomiting and anthralgia (33% each), abdominal pain and anorexia, (25% each), anemia and neutropenia (17% each). Grade >/=3 AE that occurred in =1 patient(s) included neutropenia (n=2), pneumonia (n=1) and peripheral neuropathy (n=2). According to preliminary efficacy data, disease stabilized in one patient with stomach cancer lasting >/=21 weeks. This combination of 240 mg neratinib and 25 mg/m² vinorelbine that was tolerable with early evidence of clinical benefit in patients with solid tumors, will be assessed further in patients with metastatic HEr2+ breast cancer in part 2 of this trial (Limentani SA, etal, ASCO09, Abs. e14554). Participating institutions in this trial include Carolinas Hematology Oncology Associates (Charlotte, NC), Institut Jules Bordet (Brussels, Belgium), Medische Oncologie (Wilrijk, Belgium), Highlands Oncology Group (Fayetteville, AR), Institut Curie (Paris, France), and Columbia Presbyterian Hospital (New York, NY).

A multicenter (n=22), randomized, open label, phase I/II clinical trial (protocol ID: 3144A1-2204; NCT00706030) was initiated in April 2008, in the USA, Europe (Belgium, France, Netherlands, Poland, and Spain), and Hong Kong, to evaluate the safety and efficacy of HKI-272 in combination with vinorelbine in patients with advanced solid tumors and metastatic, HEr2-positive, breast cancer previously treated with at least 1 cytotoxic chemotherapy and at least one trastuzumab-containing regimen. This phase I clinical trial is based on preclinical studies indicating a synergistic antitumor activity with the combination of trastuzumab plus vinorelbine in metastatic breast cancer, and was designed to establish a combination dose of neratinib plus vinorelbine that is tolerable in patients with solid tumors. Patients must not undergo more than 2 prior antineoplasic chemotherapy treatment regimens for metastatic disease, must not be treated with vinorelbine in metastatic setting or prior treatment with any HEr2-targeted agents except trastuzumab. The trial’s primary objectives are to identify the highest tolerable dose, safety, and to obtain preliminary information on whether the combination of the two drugs has any effect on solid tumors. According to protocol, the trial will be conducted in two parts. In part I, up to 12 patients will be tested to determine the highest tolerable dose of HKI-272 and vinorelbine. In part II, approximately 60 additional patients with no prior exposure to lapatinib, will be enrolled to better define the tolerability and preliminary activity of this regimen. Also, up to 20 additional patients with prior lapatinib exposure will be enrolled in part II for exploratory analyses. The trial is to enroll about 95 patients.

A multicenter (n=7), nonrandomized, open label, phase I clinical trial (protocol ID: 3144A1-102; NCT00146172) was conducted to assess the tolerability, safety, PK, and preliminary tumor activity of oral HKI-272 in patients (n=72) with advanced stage tumors that express EGFr or HEr2. Patients (3-6 per cohort) were administered HKI-272 (40, 80, 120, 180, 240, 320, or 400 mg) once on day 1 and then once daily beginning on day 8. Timed blood samples were collected on days 1 and 21 for PK analysis. A total of 72 patients were enrolled. All patients had been previously treated with chemotherapy regimens. Most frequently occurring tumor types at primary diagnosis were breast (n=29), non-small cell lung (n=16), colorectal (n=5), ovarian (n=6), and renal (n=3). Grade 3 diarrhea was observed in 1 patient at the 180 mg dose and in 2 patients treated at the 400 mg dose. Thus, MTD was 320 mg/day. Drug-related AE (regardless of grade, occurring in >20% of patients) were diarrhea (88%), nausea (58%), asthenia (58%), anorexia (44%), vomiting (42%), dyspnea (29%), and abdominal pain (25%). Grade 3 related AE occurring in >1 patient included diarrhea (n=22), asthenia (n=4), and vomiting (n=3). No Grade 4 drug-related AE were observed. Reasons for discontinuation included progressive disease (n=40), related AE (n=10), and unrelated AE (n=2). Cmax and AUC increased in a dose-dependent manner. At steady state at the MTD, mean values were Cmax=89.3 ng/mL; AUC=1434 ng.h/mL; t1/2=15.5 hours. Tumor assessments (modified RECIST criteria) were made at baseline and at the end of alternate cycles (28 days/cycle). PR was confirmed in 7/25 patients with breast cancer, while disease stabilized >/= 24 weeks in 1/25 patient with breast cancer, and in 5 patients with nsclc. When HKI-272 was administered on a continuous, once-daily, oral treatment schedule, the MTD was 320 mg/day, with diarrhea as the most frequently occurring related AE. HKI-272 has antitumor activity in HEr2-positive breast cancer. Phase II clinical trials of HKI-272 in patients with breast cancer and nsclc are ongoing (Wong KK, etal, ASCO06, Abs. 3018).

A multicenter (n=7), nonrandomized, open label, phase I clinical trial (protocol ID: 3144A1-102; NCT00146172), was initiated in the USA, in November 2003, to evaluate the safety of HKI-272, administered orally to patients with HEr2 or EGFr-positive tumors. The trial’s primary objective is to evaluate the safety, tolerability and to determine the MTD. Other objectives are to evaluate tumor assessment at screening and at the end of cycles 2, 4, and 6, to assess PK and PD. Approximately 88 patients were to enroll in this trial that was completed in December 2007.

Indication

non-small cell lung cancer (nsclc), advanced

Latest Status

Phase II (begin 11/05, closed 9/07) USA, Europe (France, Hungary, Poland, Spain)

Clinical History

In a phase I clinical trial, disease stabilized for >24 weeks in 6 patients with advanced non-small cell lung cancer (nsclc) and prior gefitinib or erlotinib treatment. In this 3-arm phase II clinical trial (protocol ID: 3144A1-200; NCT00266877), patients with Stage IIIb/IV or recurrent nsclc were evaluated to further characterize the safety and efficacy of neratinib. EGFr mutations were analyzed by direct sequencing. Patients with progressive disease following >12 wks of erlotinib or gefitinib and EGFr mutation were assigned to arm 1 and if wt EGFr to arm 2. Patients not previously treated with EGFr TKI with adenocarcinoma and a >20 pack-year smoking history, were assigned to group 3. The trial’s primary endpoint was objective response rate. Accrual in this trial has been completed. Preliminary data is being reported for 165 patients (T790M mutations=12/165 (7%) of whom 58% had been previously treated with 0-2 and 43% with >/=3 chemotherapy regimens. Patients were initially treated with 320 mg daily of neratinib but the protocol was amended to 240 mg because of reported gastrointestinal AE. AE of any grade related to neratinib, in >15% of patients, were diarrhea (89%), nausea (50%), fatigue (29%), anorexia (28%), vomiting (27%), abdominal pain (24%), and rash (16%). Diarrhea was the only >Grade 3 AE that occurred in ³5% of patients (320 mg=38%, 240 mg=22%). Reasons for trial discontinuation included disease progression (78%), AE (4%), and symptomatic deterioration (4%). Of the 28 patients in arm 3, 9 had EGFr mutations, 5 had no EGFr mutations, and the status of the other 14 patients was unknown. In arm 1, there were 2 PR and disease stabilized in 43 patients, lasting over 24 weeks in 14. In arm 2, there was 1 CR and disease stabilized in 22 patients, lasting more than 24 weeks in 4. In arm 3, there was 1 PR and and disease stabilized in 11 patients lasting over 24 weeks in 6. The objective response rate was 2% (4/165). None of the responders had T790M mutations. Clinical benefit rates (CR+PR+SD>24 weeks) were 18% in arm 1, 10% in arm 2, and 25% in arm 3. Median PFS was 8.9 weeks in arm 1, 8.0 weeks in arm 2, and 7.4 weeks in arm 3. Neratinib is reasonably tolerated and diarrhea was the most common >/=Grade 3 AE (Besse B, etal, EORTC-NCI-AACR08, Abs. 203). Participating institutions include Institut Gustave Roussy (Villejuif, France), University of Washington (Seattle, WA), Massachusetts General Hospital and Harvard Medical School (Boston, MA), Memorial Sloan-Kettering Cancer Center (New York, NY), Dana Farber Cancer Institute and Brigham and Women's Hospital Harvard Medical School (Boston, MA).

A multicenter (n=21), international, phase II clinical trial (protocol ID: 3144A1-200; NCT00266877) to evaluate the safety of HKI-272 in treating patients with advanced non-small cell lung cancer (nsclc) was initiated in November 2005. Approximately 165 patients were enrolled in the USA and Europe (France, Hungary, Poland, and Spain). Disease in patients in arm 1 must carry EGFr mutations demonstrated at screening. Tumors in patients in arm 2 must not carry EGFr mutations and must have progressed following >12 weeks of treatment with erlotinib or gefitinib. Patients in arm C must not have been treated with EGFr tyrosine kinase inhibitors, have adenocarcinoma, and either be a smoker or have had a ~20 pack-year smoking history. This trial was closed in September 2007.

Indication

solid tumors, advanced or metastatic, refractory

Latest Status

Phase I (begin 11/06, closed 11/08, completed 4/09) Japan, phase I (begin 11/08, closed 9/09) Japan, phase I (begin 4/09, ongoing 4/10) USA, Europe (France), phase I (begin 6/09, closed 1/10) Japan

Clinical History

A 2-center, nonrandomized, open label, phase I clinical trial (protocol ID: 3144A2-1118; NCT00958724) was initiated in June 2009, in Japan, to evaluate the safety and efficacy of neratinib in combination with vinorelbine in treating patients with advanced or metastatic solid tumors. The trial’s primary objective is to confirm the safety and tolerability. Secondary objectives are to obtain preliminary data describing antitumor activity and to assess PK. The trial, to enroll about 12 patients, was closed in January 2010.

A phase I clinical trial (protocol ID: 3144A1-104; NCT00397046) was conducted in Japan, at the Cancer Institute Hospital, in Tokyo and the Shizuoka Cancer Center, to determine MTD, safety and preliminary efficacy in Japanese patients with advanced solid tumors. According to the protocol, cohorts of 3 to 6 patients are treated with oral neratinib at a dose of 80, 160, 240, or 320 mg. Each patient participated in only one dose group and treated with single doses of neratinib followed by 1 week of observation; subsequently patients were treated with daily continuous neratinib at the same dose. DLT were assessed from the first single dose to the end of 14 days of continuous treatment. PK were analyzed by a non-compartmental method. Tumor measurements were made at screening and at the end of every 8 weeks (2 cycles) by RECIST. Preliminary data as of October 30, 2008, is based on 21 patients who had been previously treated with >/=2 prior chemotherapy regimens. Tumor types at primary diagnosis were advanced colorectal cancer (81%), breast cancer (14%), and gastric cancer (5%). Median duration of neratinib treatment was 10 (range=3-29) weeks. There were 2 DLT at the 320 mg dose, diarrhea plus anorexia. Therefore, the MTD was determined to be 240 mg. Neratinib-related AE of any grade noted in >/=25% of patients included diarrhea (95%), fatigue (67%), anorexia (43%), nausea (43%), abdominal pain (38%), decreased hemoglobin (38%), increased AST (33%), and rash (29%). Grade >/=3 neratinib-related AE, in >/=1 patients were anorexia (n=3) and diarrhea (n=2). There were 2 PR in patients with HEr2-positive advanced breast cancer, disease stabilized in 8 patients for >/=8 weeks and in 2 patients for 16 weeks, and progressed in 9. In Japanese patients, the MTD and recommended neratinb dose was determined to be 240 mg (Ito Y, etal, ASCO09, Abs. e14505).

A multicenter (n=4), nonrandomized, open label, single group assignment, phase I clinical trial (protocol ID: 3144A1-2205; NCT00838539) was initiated in April 2009, in the USA and Europe (France), to evaluate the efficacy and MTD of neratinib in combination with temsirolimus in patients with advanced or metastatic solid tumors. Patients must have incurable cancer with disease progression following at least 1 conventional or standard therapy for locally advanced or metastatic disease, must not have primary CNS metastases, and must not have prior history of non-infectious interstitial pneumonitis or significant chronic or recent acute gastrointestinal disorder. The trial’s primary outcome measure is to determine the MTD of this combination and secondary outcome measure is to assess the preliminary efficacy, PK, and additional safety. This trial is to enroll about 32 patients.

A 2-center, open label, single group assignment, phase I clinical trial (protocol ID: 3144A2-1115; NCT00768469) was initiated in November 2008, in Japan, to evaluate the safety if HKI-272 in combination with paclitaxel in treating patients with solid tumors not curable with available therapy. Patients must not undergo treatment with anthracyclines, must not have active CNS metastases, and must not have hypersensitivity to paclitaxel. The trial’s primary objectives are to assess the safety and tolerability, and to determine the recommended dose. Secondary objectives are to obtain preliminary anti-tumor activity and PK. The trial is to enroll about 18 patients. This trial was closed in September 2009.

A nonrandomized, open label, phase I clinical trial (protocol ID: 3144A1-104; NCT00397046) was initiated in Japan, in November 2006, to evaluate the safety and efficacy of HKI-272 administered PO to Japanese patients with advanced solid tumors. The trial’s primary objectives are to assess the tolerability, safety and efficacy of HKI-272 and to determine MTD. According to the protocol, each patient participates in only 1 dose group, and is administered a single dose of HKI-272, followed by a 1-week observation period, and then once daily PO in cycles consisting of 28 days. Patients are enrolled in cohorts of 3 to 6. AE and DLT are assessed from the first single dose. This trial, to enroll 28 patients, has been reported closed as of November 2008, and completed in April 2009.

Indication

breast cancer, advanced (Stage IIIb/c) or metastatic (Stage IV), overexpressing HEr2, refractory

Latest Status

Phase II (begin 3/06, closed 11/07) USA, Brazil, China, Europe (Belgium, France, Netherlands, Russia), India, Mexico; phase I/II (begin 8/07, closed 2/09) USA, Canada, China, Europe (Belgium, Poland, Ukraine), Hong Kong , India, Korea (combination), phase I/II (begin 10/08, ongoing 4/10) USA, Europe (Hungary, Spain), Hong Kong (combination), phase I/II (begin 3/07, closed 3/08) USA, China, Europe (France, Spain, Switzerland), South Africa (combination); phase III (begin 11/08, ongoing 4/10) USA, Europe (Hungary, Serbia, Spain), Hong Kong, Puerto Rico

Clinical History

The open label, 2-part clinical trial (protocol ID: 3144A1-203; NCT00445458) enrolled patients with solid tumors in part 1 to determine the MTD and patients with HEr2+ metastatic breast cancer in the 1st to 4thline setting in part 2, to determine the objective response rate (ORR). In part 1, patients were treated with ascending oral dosages of neratinib (160 mg or 240 mg) plus IV paclitaxel (80 mg/m²) on days 1, 8, and 15 of a 28-day cycle. In part 2, patients were treated with neratinib plus paclitaxel at the MTD. Tumor response was assessed using modified RECIST criteria. Safety and PK parameters were also evaluated. Full doses of neratinib (240 mg) and paclitaxel (80 mg/m²) were well tolerated in part 1 and evaluated in part 2. As of October 19, 2009, data were available for 102 patients enrolled in part 2. The most common treatment-emergent AE were diarrhea (91%), neutropenia (53%), alopecia (48%), peripheral neuropathy (46%), and leukopenia (44%). Common Grade 3 AE included diarrhea (28%), leukopenia (21%), and neutropenia (21%). Diarrhea generally occurred early (median onset=3 days after neratinib initiation; median duration=30 days); 3 patients withdrew because of AE (renal failure, LVEF reduction). PK evaluation suggested no drug interaction; exposures were similar to each drug as monotherapy. Among 99 evaluable patients, the ORR (CR+PR) in part 2 was 69% (CR=4% and PR=64%). Median PFS is estimated at 52.1 weeks. The ORR was better in women with hormone receptor positive tumors (84% versus 50%; p<0.05). Responses were observed in 31 of 39 patients with prior endocrine therapy (ORR=80%), 47 of 62 patients with prior taxane therapy (ORR=76%), and 10 of 14 patients with prior lapatinib therapy (ORR=71%), and and prior taxane therapy (ORR=76%) in any setting or line of therapy. Neratinib (240 mg) plus paclitaxel (80 mg/m²) was tolerable, with a similar toxicity profile to each drug administered as monotherapy. The differential clinical activity observed in this setting with respect to prior treatment supports further investigation of patient subsets (Chow L, etal, IMPAKT10. Abs. 144P).

In the phase II part of a phase I/II clinical trial (protocol ID: 3144A1-202; NCT00398567) that assessed the safety and preliminary efficacy of the combination of neratinib plus trastuzumab, the preliminary objective response rate was 26% in patients with HEr2+ advanced breast cancer that progressed following trastuzumab therapy. The primary endpoint was 16-week PFS. In part 1 (dose escalation), patients were treated with neratinib at a dose of 160 mg or 240 mg daily plus IV trastuzumab at a loading dose of 4 mg/kg and then at 2 mg/kg weekly. In part 2, patients are treated with weekly trastuzumab plus daily neratinib (240 mg). Timed blood samples were collected for PK analyses. Among 45 patients (part 1=8 and part 2=37) enrolled, 9 are still being treated. In part 1, cohorts 1 and 2 were fully enrolled with 4 patients each. There were no DLT. Most common AE of any grade, were diarrhea (91%), nausea (51%), anorexia (40%), vomiting (38%), and asthenia (27%). Grade 3/4 AE were diarrhea (13%), nausea (4%), vomiting (4%). Two patients treated with neratinib at the 240 mg dose reported AE leading to withdrawal. No AE of congestive heart failure and no significant drops of left ventricular ejection fraction were reported. Among 33 patients evaluable for efficacy, the objective response rate was 27% (95% CI, 13%-46%), the 16-week PFS rate (for part 2) was 47% (95% CI, 29%-63%), and median PFS was 19 weeks (95% CI 15-32 weeks). Neratinib plus trastuzumab was well tolerated with no significant or unexpected toxicities, and demonstrated clinical activity (Swaby R, etal, ASCO09, Abs. 1004). Participating institutions included Fox Chase Cancer Center (Philadelphia, PA), Duke Breast Oncology Program (Durham, NC), Hospital of the Chinese People's Liberation Army (Beijing, China), Cancer Hospital, Chinese Academy of Medical Sciences (Beijing, China), Institut Curie (Paris, France); and the University Hospital CHUV (Lausanne; Switzerland).

The multicenter (n=9), nonrandomized, open label, phase I/II clinical trial (protocol ID: 3144A1-203; NCT00445458) was conducted in 2 parts. In part 1, ascending multiple daily oral doses of neratinib (160 mg or 240 mg) were administered in combination with IV paclitaxel (80 mg/m²), if tolerable, or 70 mg/m² on days 1, 8 and 15. Patients with solid tumors were enrolled in part 1 and patients with only metastatic HEr2+ breast cancer enrolled in part 2. Tumor measurements were made at screening and at every 8 weeks (2 cycles) by modified RECIST. Timed blood samples were collected for neratinib and paclitaxel plasma concentration determination, and PK analyses were performed using a noncompartmental method. As of October 30, 2008, data was available on 54 patients; 26 % had been previously treated with trastuzumab and 15% with lapatinib. Tumor types in part 1 included breast, endometrial, cervical, colorectal and esophageal cancer. There were no DLT at the 240 mg neratinib-80 mg/m² paclitaxel dose, and as standard doses of neratinib and paclitaxel were reached, there was no reason for further escalation. Neratinib-related AE, any grade in >/=10% of patients included diarrhea (50%), neutropenia (17%), rash (13%), nausea (11%) and vomiting (11%). Neratinib- related AE, Grade >/=3 in >/=2% of patients were diarrhea (20%), neutropenia (9%) and dehydration (4%). Only 2 patients (at the 240 mg neratinib-80 mg/m² paclitaxel dose) required dose reductions because of diarrhea. In 35 efficacy-evaluable patients, there were 5 confirmed PR. Confirmed clinical benefit (PR and prolonged disease stabilization) was seen in 2 patients in part 1, 1 patient with endometrial cancer and 1 with cervical cancer. This combination of 240 mg neratinib and 80 mg/m² paclitaxel was tolerable with a toxicity profile similar to that observed for neratinib, and had promising antitumor activity in patients with solid tumors and HEr2+ breast cancer (Chow L, etal, ASCO09, Abs. 3557). Participating institutions included UNIMED Medical Institute (Hong Kong, China), No. 307 Hospital of the People's Liberation Army (Beijing, China), Queen Mary Hospital (Hong Kong, China), City Multifield Clinical Hospital #4 (Dnipropetrovsk, Ukraine), Institut Jules Bordet (Brussels, Belgium), and Columbia Presbyterian Hospital (New York, NY).

A multicenter (n=111), randomized, open label, phase III clinical trial (protocol ID: 3144A2-3003; NCT00777101) was initiated in November 2008, in the USA, Europe (Hungary, Serbia, Spain), Hong Kong, and Puerto Rico, to evaluate the safety and efficacy of HKI-272 versus lapatinib plus capecitabine in treating patients with ErbB-positive, HEr2-positive, locally advanced (Stage IIIb/IIIc) or metastatic (Stage IV) breast cancer previously treated with trastuzumab, an anthracycline, and a taxane. Patients must not undergo treatment with more than 2 prior regimens of trastuzumab, must not undergo prior treatment with capecitabine, and must not have active CNS metastases. The trial’s primary objective is to determine PFS. Secondary objective is to assess AE. The trial is to enroll about 1000 patients.

A multicenter (n=20), nonrandomized, open label, phase I/II clinical trial (protocol ID: 3144A1-2206; NCT00741260) was initiated in October 2008, in the USA, Europe (Hungary, Spain), and Hong Kong, to evaluate the safety and efficacy of HKI-272 in combination with capecitabine in treating patients with solid tumors or HEr2-positive, metastatic or locally advanced breast cancer. Patients must not have active CNS metastases, must not have other cancer within 5 years prior to screening except cervical carcinoma in situ or adequately treated basal or squamous cell carcinoma of the skin, and patients in part II must not be treated with capecitabine, anthracyclines with a cumulative dose of doxorubicin of greater than 400 mg/m², or any HEr2-targeted agents except trastuzumab. The trial’s primary objectives are to assess the safety and tolerability and to determine the MTD. Secondary objectives are to collect information on preliminary antitumor activity, PK, and additional efficacy data. According to protocol, the trial will be conducted in two parts. In part I, 3 to 6 patients with solid tumors will be enrolled in each dose group of the combination of HKI-272 and capecitabine. Each patient will participate in only 1 dose group. Additional patients may be included at any dose level to further assess the safety and tolerability at that dose level. During part II, up to 60 patients with HEr2-positive metastatic breast cancer will be administered treatment with the combination of HKI-272 and capecitabine at the MTD, as determined in part I. Depending on the safety and activity profile observed during the dose escalation phase, the dose selected for part II may be adjusted, if appropriate. In case one test article of the combination is discontinued due to intolerance, the other test article can be administered alone. The trial is to enroll about 60 patients.

Results reported at the CTRC-AACR San Antonio Breast Cancer Symposium from the open label, 2-arm phase II clinical trial (protocol ID: 3144A1-201; NCT00300781) of neratinib (HKI-272) suggest that neratinib has antitumor activity in patients with advanced HEr2-positive breast cancer. The phase II clinical trial evaluated the safety and efficacy of a daily PO neratinib (240 mg) in 136 women diagnosed with HEr2-positive locally advanced or metastatic breast cancer (Stage IIIb, IIIc or IV). The trial’s primary endpoint was the 16-week PFS rate. Secondary endpoints included safety, objective response rate (ORR) in terms of CR and PR and CBR in terms of objective response plus stable disease. Patients were assigned to one of two arms based on prior treatment with trastuzumab (Herceptin; Genentech). A total 136 women were enrolled in this trial. Women enrolled in arm A (n=66) had either previously been treated for at least 6 weeks with a standard trastuzumab regimen or had experienced disease progression during or following trastuzumab-containing adjuvant therapy. Women in arm B (n=70) had not been previously treated with any HEr2-targeted therapy, including trastuzumab. The efficacy analysis included 127 evaluable patients, 61 in arm A and 66 in arm B. In patients previously treated with trastuzumab (arm A), the 16-week PFS rate was 60%, and the median PFS was 23 weeks, as evaluated by independent assessment. ORR was 26%, and CBR was 36%. In trastuzumab-naïve patients (arm B), the 16-week PFS rate was 77%, and the median PFS was 40 weeks by independent assessment. ORR was 56%, and CBR was 68%. AE of any grade occurring in more than 15% of patients included diarrhea, nausea (29%), vomiting (23%), fatigue (16%), anorexia (15%), abdominal pain, headache and rash. Diarrhea was the most common toxicity, reported in 93% of patients. Diarrhea was also the most significant Grade 3 or 4 AE, occurring in 21% of patients; Grade 3 diarrhea, the only Grade 3 AE that occurred in 26/136 (5%) patients (arm A=27%, and arm B=11%). Diarrhea was reversible and generally manageable by medication, treatment interruption or dose reduction. Dose reductions were necessary in 27% of patients, 36% in arm A and 19% in arm B, mostly commonly because of diarrhea., and 1patient discontinued treatment because of diarrhea. The chief reasons for treatment discontinuation were disease progression (arm A=74%, arm B=43%), and AE (arm A=8%, arm B=4%). Based on these findings, neratinib demonstrates robust antitumor activity in patients with HEr2-positive advanced breast cancer (Burstein H, etal, SABCS08, Abs 37).

A multicenter (n=42), nonrandomized, open label, phase I/II clinical trial (protocol ID: 3144A1-203; NCT00445458) was initiated in August 2007, in the USA, Canada, China, Europe (Belgium, Poland, Ukraine), Hong Kong , India, and Korea, to evaluate the safety and efficacy of HKI-272, in combination with paclitaxel, in patients with advanced solid tumors or breast cancer. Primary outcome measures are physical exams, adverse event assessments, and radiographic tumor assessments (CT, MRI, bone scan). Secondary outcome measures are ECG/ECHO/MUGA lab values. According to the protocol, the trial is being conducted in 2 parts. During the first part, testing will be done to determine MTD of HKI-272 and paclitaxel. During the second part, patients with HEr2-positive breast cancer, previously treated with trastuzumab, will be enrolled to further test the safety of the drug combination, and to obtain preliminary data on its efficacy. The trial will enroll about 93 patients. This trial was closed in February 2009.

A multicenter (n=20), nonrandomized, open label, phase I/II clinical trial (protocol ID: 3144A1-202; NCT00398567) was initiated in March 2007, in the USA, China, Europe (France, Spain, Switzerland), and South Africa, to evaluate the safety and tolerability of neratinib in combination with trastuzumab in patients with HEr2-positive, advanced (Stage IIIb or IIIc) or metastatic (Stage IV) breast cancer. Patients must not undergo more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease, must not have prior exposure to neratinib or other HEr2-targeted agents, and must not have inflammatory breast disease or life-threatening hypersensitivity to trastuzumab. The trial’s primary outcome measure is to determine the safety, efficacy, and AE. According to the protocol, 3-6 patients are enrolled in each dose group. AE and DLT will be assessed from the first dose though day 21. When the MTD of neratinib plus trastuzumab is determined, an additional 30 patients will be enrolled at that dose level, and followed for PFS for approximately 1 year. This trial, to enroll about 45 patients, was closed in March 2008.

A multicenter (n=41), international, phase II clinical trial (protocol ID: 3144A1-201; NCT00300781) was initiated In March 2006, in the USA, Brazil, China, Europe (Belgium, France, Netherlands, Russia), India, and Mexico, to evaluate the safety and efficacy of HKI-272 in treating women with advanced (Stage IIIb/c) or metastatic breast cancer with tumors overexpressing HEr2. HEr2 gene amplification in tumor tissue, by FISH was a requirement for study entry. Approximately 122 patients are to be enrolled in this trial. In arm A, patients have disease that progressed following at least 6 weeks of standard doses of Herceptin In arm B, patients were not previously treated with Herceptin or HEr2-targeted drugs. This trial was reported closed as of November 2007. Participating institutions included the Cleveland Clinic, Dana-Farber Cancer Institute (Boston, MA), under PI Harold Burstein, MD, PhD; Cancer Institute and Hospital, Chinese Acadeny of Medical Sciences; Cancer Institute of New Jersey (New Brunswick, NJ); Oncology Center AZ St-Augustinus (Antwerp, Belgium); Tata Memorial Hospital (Mumbai, India), among others.

Indication

breast cancer, early stage (Stage I/IIIc), HEr2 positive • breast cancer, locally advanced or metastatic, HEr2 positive, first line

Latest Status

Phase III (begin 6/09, ongoing 4/10) USA, Bahamas, phase III (begin 6/09, ongoing 4/10) USA (combination)

Clinical History

A randomized, open label, phase III clinical trial (protocol ID: 3144A2-3005; NCT00915018) was initiated in June 2009, in the USA, to compare neratinib in combination with paclitaxel versus trastuzumab in combination with paclitaxel as first line treatment in patients with HEr2-positive, locally recurrent or metastatic breast cancer. Patients must not undergo prior treatment with a HEr2 inhibitor other than trastuzumab or lapatinib in the neoadjuvant or adjuvant setting, must not have progression or recurrence within 12 months after completion of adjuvant or neoadjuvant therapy, and must not have history of heart disease or gastrointestinal disease. The trial’s primary outcome measures are to determine the PFS and OS. This trial is to enroll about 1200 patients.

A multicenter (n=17), randomized, double blind, parallel assignment, phase III clinical trial (protocol ID: 3144A2-3004; NCT00878709) was initiated in June 2009, in the USA and Bahamas, to evaluate the effects of neratinib versus placebo in patients with early stage (Stage I/IIIc), HEr2-positive breast cancer. Patients must have undergone prior treatment with trastuzumab for early breast cancer, must have positive clinical and radiologic assessments for local or regional recurrence of disease at the time of entry, and must not have history of heart disease or gastrointestinal disease. The trial’s primary outcome measure is to determine the disease free survival and secondary outcome measure is to evaluate AE. This trial is to enroll about 3,850 patients.

Indication

breast cancer, locally advanced, HEr2-positive, neoadjuvant

Latest Status

Phase II (begin 3/10) USA (combination)

Clinical History

A randomized, open label, phase II clinical trial (protocol ID: NSABP FB-7; NCT01008150) was initiated in February 2010, in the USA, sponsored by the National Surgical Adjuvant Breast and Bowel Project (NSABP), to evaluate neoadjuvant therapy regimens with paclitaxel in combination with neratinib or trastuzumab followed by doxorubicin and cyclophosphamide (AC) with postoperative trastuzumab in treating female patients with locally advanced, HEr2-positive breast cancer. The trial’s primary objective is to determine pathologic CR in breast and axillary lymph nodes. Secondary objectives are to assess clinical CR, pathologic CR in breast, recurrence-free survival, OS, and to evaluate toxicity. According to the protocol, patients are randomized to the control arm (arm A) or to the investigational arm (arm B) in a 1:2 ratio. Patients in arm A will be treated with 4 cycles of paclitaxel (80 mg/m²) administered on days 1, 8, and 15 of a 28-day cycle. Trastuzumab begins concurrently with paclitaxel and is administered weekly for a total of 16 doses (4 mg/kg loading dose, then 2 mg/kg weekly). Following paclitaxel/trastuzumab, standard AC is administered every 21 days for 4 cycles. Patients in arm B are treated with 4 cycles of paclitaxel (80 mg/m²) administered on days 1, 8, and 15 of a 28-day cycle. Neratinib (240 mg) is administered orally once daily beginning on day 1 of paclitaxel and continuing through day 28 of the final cycle of paclitaxel. Standard AC is administered every 21 days for 4 cycles following paclitaxel/neratinib therapy. In both arms, clinical response are assessed by palpation between the chemotherapy regimens and prior to surgery. Following recovery from surgery, trastuzumab (8 mg/kg loading dose, then 6 mg/kg) is administered every 3 weeks to complete 1 year of targeted therapy (either preoperative trastuzumab therapy or neratinib therapy). Patients are administered adjuvant radiation therapy and endocrine therapy as clinically indicated. The trial will enroll about 120 patients.

Also see record for I-SPY 2 trial (protocol ID: NCT01042379) in Combination Trials module

Current as of

May 16, 2010