Arm Experienced Grade Research Articles

Safety analysis for BH009 vs docetaxel from a bioavailability study.

e13129 Background: BH009 is a novel polysorbate 80-free formulation of docetaxel (DXT) that could eliminate hypersensitivity reactions associated with polysorbate 80. In a bioavailability study of BH009 vs docetaxel (Taxotere), we reported that the ratios for the total DXT and free-DXT fraction Cmax, AUC0-t, and AUC0-∞ of BH009 and docetaxel were within 80% to 125% (90% confidence intervals). Here, we report the safety analysis from the same study population. Methods: This multicenter, randomized, open-label, 2-way crossover study compared the pharmacokinetics and safety of BH009 and docetaxel (Winthrop docetaxel injection, an authorized generic of Taxotere). A total of 46 patients with breast, head and neck, lung, stomach, ovarian, or cervical cancers were randomized, of which 43 patients were treated with BH009 and 44 patients were treated with docetaxel. Patients received a single dose of 75 mg/m2 BH009 or Taxotere IV over 60 min, with ≥21-d washout between doses. Safety evaluation included treatment-emergent adverse events (TEAEs) and serious adverse events. Results: In all, 198 TEAEs were reported during the study: 94 after the administration of BH009 and 104 after the administration of docetaxel. No serious adverse events or deaths occurred. The only grade 3/4 toxicities that occurred for both arms during this study were hematologic. Overall, the incidence of grade 3/4 hematologic toxicity was significantly lower in the BH009 group than in the docetaxel group (2.3% vs 15.9%). Only one patient in BH009 arm experienced grade 3 anemia; no additional grade 3/4 hematologic adverse events were seen in the BH009 group. The incidence of grade 3/4 leukopenia, neutropenia, and lymphopenia in the Taxotere group was 6.8%, 4.6%, and 2.3%, respectively. The overall safety profile in the BH009 group was better than that in the Taxotere group. Conclusions: A better safety profile was observed in the study when BH009 group was compared to docetaxel group in grade 3/4 hematologic toxicity. Clinical trial information: NCT04889599 . [Table: see text]

Tislelizumab plus chemotherapy (chemo) versus placebo plus chemo as first-line treatment for locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: RATIONALE-305 European/North American patient subgroup.

330 Background: Tislelizumab (TIS), an anti-programmed cell death protein 1 monoclonal antibody, plus chemo, demonstrated significant overall survival (OS) benefit vs placebo (PBO) plus chemo (15.0 vs 12.9 months [mo], hazard ratio [HR]=0.80, 95% confidence interval [CI]: 0.70, 0.92, P=0.0011) as first-line therapy in patients (pts) with advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) in the randomized, double-blind, global, phase 3 RATIONALE-305 study (NCT03777657). Here we present results from the European/North American (Eu/NA) pts subgroup analysis. Methods: This double-blind, global, phase 3 study evaluated adult pts with previously untreated, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable, or metastatic GC/GEJC, regardless of programmed death-ligand 1 (PD-L1) expression status. Eligible pts were randomized (1:1) to receive TIS 200 mg or PBO intravenously once every 3 weeks plus investigator chosen chemo (5-fluorouracil + cisplatin or capecitabine + oxaliplatin). The primary endpoint was OS in the PD-L1+ (patients with tumor area positivity score ≥5%) and intent-to-treat (ITT) analysis sets. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Results: Of 997 pts enrolled, 249 (25.0%) were from Eu/NA (TIS plus chemo arm, n=125; PBO plus chemo arm, n=124). In the Eu/NA pts subgroup, after a minimum follow-up of 26.6 mo at final analysis, TIS plus chemo resulted in OS improvements vs PBO plus chemo in the PD-L1+ (HR=0.75, [95% CI: 0.52, 1.07]; 24 mo rate 27.6% vs 12.5%) and ITT analysis sets (HR=0.71, [95% CI: 0.54, 0.94]; 24 mo rate 27.6% vs 13.6%). TIS plus chemo resulted in favorable PFS vs PBO plus chemo (HR=0.84, 95% CI: 0.63, 1.11), numerically higher ORR (36.0% vs 31.5%), and longer DoR (median 7.5 mo [95% CI: 4.4, 12.0] vs 5.0 mo [95% CI: 3.9, 6.7]). Sixty (48.8%) pts in the TIS plus chemo arm and 61 (49.2%) pts in the PBO plus chemo arm experienced grade ≥3 treatment-related treatment-emergent adverse events (TRAEs). Sixteen (13.0%) and seven (5.6%) pts discontinued treatment due to TRAEs in the TIS plus chemo and PBO plus chemo arms, respectively. Deaths due to TRAEs occurred in two (1.6%) pts in the TIS plus chemo arm and one (0.8%) pt in the PBO plus chemo arm. Conclusions: TIS plus chemo showed OS benefit compared with PBO plus chemo and a manageable safety profile in pts in the Eu/NA subgroup with previously untreated, HER2-negative, locally advanced unresectable, or metastatic GC/GEJC. These findings are consistent with the published results in the overall study population. Clinical trial information: NCT03777657 .

Abstract PD18-03: Final analysis of the Phase III PEONY trial: long-term efficacy and safety of neoadjuvant–adjuvant pertuzumab or placebo, plus trastuzumab and docetaxel, in patients with HER2-positive early or locally advanced breast cancer

Abstract BACKGROUND In the Phase II NeoSphere study (NCT00545688), dual HER2 blockade with pertuzumab (P) + trastuzumab (H), + docetaxel (D) significantly increased pathologic complete response (pCR) vs. H+D in the neoadjuvant setting for HER2-positive early breast cancer (EBC), locally advanced (LA) BC, or inflammatory BC, with supportive progression- and disease-free survival (DFS) data. Consistently, the randomized, multicenter, double-blind, placebo (Pla)-controlled Phase III PEONY trial (NCT02586025) significantly improved total pCR (tpCR; primary endpoint) with P+H+D vs. H+D in an Asian population, and safety data were in-line with the known P safety profile. We present the final analysis of long-term efficacy (at 3 and 5 years) and safety from the study. METHODS Patients had centrally confirmed HER2-positive EBC (T2–3, N0–1) or LABC (T2–3, N2 or N3; T4, any N) and were randomized 2:1 to four neoadjuvant P+H+D or Pla+H+D cycles every 3 weeks. P: 840 mg loading/420 mg maintenance doses (or Pla); H: 8 mg/kg loading/6 mg/kg maintenance; D: 75 mg/m2. Patients then received three fluorouracil, epirubicin, and cyclophosphamide cycles, followed by 13 of P+H or Pla+H in the adjuvant setting for up to 1 year. Long-term outcomes (event-free survival [EFS], DFS, overall survival [OS]; all secondary endpoints) were assessed by Kaplan–Meier methods, Cox proportional hazards models, and a two-sided log-rank test (stratified by disease category and hormone receptor status). RESULTS Data cut-off was Mar 14, 2022, and 329 patients were randomized; 219 to P; 110, to Pla. Safety populations were 218 and 110 patients, respectively. Baseline characteristics were well balanced. Most patients received the full HER2-targeted cycles. Median follow-up was 62.9 months. Long-term efficacy data are shown in the table. During the overall treatment period, 70.6% of patients in the P+H+D arm and 68.2% in the Pla+H+D arm experienced grade ≥3 adverse events (AEs); the most common (in ≥5% of patients in either arm) being neutropenia (59.2% vs. 55.5%), leukopenia (34.4% vs. 34.5%), and febrile neutropenia (5.0% vs. 3.6%). Of the most common any-grade AEs (in ≥30% of patients in either arm), diarrhea was more common in the P+H+D arm (40.8% vs. 17.3% in the Pla+H+D arm). Serious AEs were reported in 17.0% and 13.6% of patients, respectively. No primary cardiac events (heart failure [New York Heart Association grade III or IV] or significant decline of left ventricular ejection fraction) or secondary cardiac events occurred during any study periods. CONCLUSIONS Long-term efficacy endpoints (EFS, DFS, and OS) were supportive of the primary endpoint results (tpCR) and suggested a clinically meaningful improvement with P+H vs. Pla+H when administered before and after surgery for one year of anti-HER2- therapy. Safety data were in-line with the known P safety profile and generally comparable between arms, with the exception of diarrhea. PEONY adds to the totality of data showing the benefit of the P+H+D regimen in HER2-positive EBC. Table 1: Long-term efficacy data Citation Format: Zhi-Ming Shao, Da Pang, Hongjian Yang, Wei Li, Shusen Wang, Shude Cui, Ning Liao, Yong-Sheng Wang, Chuan Wang, Yuan-Ching Chang, Hwei-Chung Wang, Seok Yun Kang, Jae Hong Seo, Kunwei Shen, Suphawat Laohawiriyakamol, Zefei Jiang, Liang Huang, Haiyan Wang, François Lamour, Grace Song, Eleonora Restuccia. Final analysis of the Phase III PEONY trial: long-term efficacy and safety of neoadjuvant–adjuvant pertuzumab or placebo, plus trastuzumab and docetaxel, in patients with HER2-positive early or locally advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-03.

Abstract P3-06-07: Phase Ib/II study to evaluate safety and tolerability of cabiralizumab in combination with nivolumab and neoadjuvant chemotherapy in patients with localized triple-negative breast cancer

Abstract Background: Neoadjuvant immune checkpoint inhibition (ICI) in combination with chemotherapy is approved for patients with high-risk, early-stage triple-negative breast cancer (TNBC) based on improved outcomes in the KEYNOTE-522 trial. However, some patients have primary resistant disease and do not achieve a pathological complete response (pCR), while others experience significant toxicity. Tumor-associated macrophages (TAMs) are a potential resistance mechanism for ICIs and are dependent on colony-stimulating factor 1 receptor (CSF1R). Therefore, we examined the addition of cabiralizumab, a CSF1R inhibitor, to neoadjuvant paclitaxel, carboplatin, and nivolumab to assess the safety, tolerability, and changes in the tumor microenvironment (TME) in patients with early-stage TNBC. Methods: This is a phase Ib/II, single-institution, randomized controlled clinical trial (NCT04331067) in patients with newly diagnosed Stage II-III TNBC. The primary endpoints include: (1) to determine the safety of a 12-week neoadjuvant regimen of paclitaxel (80 mg/m2 IV q week) + carboplatin (AUC5 IV q3 weeks) + nivolumab (240 mg IV q2 weeks) with or without cabiralizumab (4 mg/kg IV q2 weeks) and (2) to evaluate the effect of cabiralizumab on TAMs and changes in tumor infiltrating lymphocytes (TILs) in the TME between baseline and an on-treatment biopsy after 4 weeks of therapy. Adjuvant treatment is per investigator’s choice. Secondary objectives include evaluation of pCR rate and recurrence-free survival. Paired tissue and bone marrow biopsies are collected for evaluation of the TME and disseminated tumor cells, respectively. The study was designed to enroll 50 patients, including a 12-patient safety lead-in cohort. Here, we report the planned interim analysis of the safety lead-in cohort. Results: Between December 2020 and May 2022, we enrolled 12 patients to the safety lead-in, including 6 patients in each arm. 5 of 12 patients (41.7%) enrolled are underrepresented minorities, including 4 Black patients and 1 Hispanic patient. 2 of 6 patients in the nivolumab arm experienced grade 3 severe toxicity, including 1 patient who developed sepsis and 1 who developed peripheral neuropathy. 3 of 6 patients in the nivolumab + cabiralizumab arm developed grade 3 severe toxicity including 2 patients who experienced myositis and 1 patient who developed periorbital edema. Of the first 10 patients enrolled, 5 had a pCR (2 pCR in cabiralizumab arm, 3 pCR in non-cabiralizumab arm) and 3 had non-pCR (1 RCB-1 and 1 RCB-3 in cabiralizumab arm, 1 RCB-1 in non-cabiralizumab arm). 2 patients came off study prior to surgery (1 due to toxicity and 1 due to missing study visits). Data from the final 2 patients still on treatment will be available at the time of presentation. Discussion: Full safety, pathologic, and clinical response data in the safety lead-in cohort for patients with early-stage TNBC receiving neoadjuvant chemotherapy + nivolumab with or without cabiralizumab, will be presented. Citation Format: Andrew A. Davis, Leonel Hernandez-Aya, Jingqin Luo, Mateusz Opyrchal, Foluso O. Ademuyiwa, Nusayba A. Bagegni, Katherine K. Clifton, Jill Anderson, Trish Hammerschmidt, Leslie Nehring, David DeNardo, Mark Watson, Rebecca Aft, Cynthia Ma, Katherine Weilbaecher. Phase Ib/II study to evaluate safety and tolerability of cabiralizumab in combination with nivolumab and neoadjuvant chemotherapy in patients with localized triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-07.

LUSTRE: A Phase III Randomized Trial of Stereotactic Body Radiotherapy (SBRT) vs. Conventionally Hypofractionated Radiotherapy (CRT) for Medically Inoperable Stage I Non-Small Cell Lung Cancer (NSCLC)

LUSTRE: A Phase III Randomized Trial of Stereotactic Body Radiotherapy (SBRT) vs. Conventionally Hypofractionated Radiotherapy (CRT) for Medically Inoperable Stage I Non-Small Cell Lung Cancer (NSCLC)

A randomized phase-II study of reirradiation and hyperthermia versus reirradiation and hyperthermia plus chemotherapy for locally recurrent breast cancer in previously irradiated area

Background In patients with inoperable local regional recurrences of breast cancer in previously irradiated areas, local control is difficult to maintain and treatment options are limited. The Dutch standard treatment for such recurrences is reirradiation combined with hyperthermia. Apart from enhancing the effect of reirradiation, hyperthermia is also known to improve local effects of chemotherapy like cisplatin. This randomized phase-II trial compares reirradiation and hyperthermia versus the same treatment combined with cisplatin. Patients and methods From December 2010 up to January 2019, 49 patients were randomized, 27 in the standard arm and 22 in the combined arm. A total of 32 Gy was given in eight fractions of 4 Gy in 4 weeks, at two fractions per week. After January 2015, the radiation schedule was changed to 46 Gy in 23 fractions of 2 Gy, at five fractions per week. Hyperthermia was added once a week after radiotherapy. The combined arm was treated with four cycles of weekly cisplatin 40 mg/m2. Results Complete response rate was 60.9% in the standard arm and 61.1% in the combined arm (p = 0.87). Partial response rate was 30.4% in the standard arm and 33.3% in the combined arm (p = 0.79). One-year overall survival was 63.4% in the standard arm and 57.4% in the combined arm. One-year local progression-free interval was 81.5% in the standard arm and 88.1% in the combined arm (p = 0.95). Twenty-five percentage of patients in the standard arm experienced grade 3 or 4 acute toxicity and 29% of patients in the combined arm (p = 0.79). Conclusion No potential benefit could be detected of adding cisplatin to reirradiation and hyperthermia in patients with recurrent breast cancer in a previously irradiated area. With or without cisplatin, most patients had subsequent local control until last follow-up or death.

Sustained Overall Survival Benefit of Obinutuzumab Plus Bendamustine Followed By Obinutuzumab Maintenance Compared with Bendamustine Alone in Patients with Rituximab-Refractory Indolent Non-Hodgkin Lymphoma: Final Results of the Gadolin Study

Sustained Overall Survival Benefit of Obinutuzumab Plus Bendamustine Followed By Obinutuzumab Maintenance Compared with Bendamustine Alone in Patients with Rituximab-Refractory Indolent Non-Hodgkin Lymphoma: Final Results of the Gadolin Study

Hematologic Improvement-Neutrophil and -Platelet in the MEDALIST Trial: Multilineage Data from a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions

Hematologic Improvement-Neutrophil and -Platelet in the MEDALIST Trial: Multilineage Data from a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions

Effects of Surgery With Salvage Stereotactic Radiosurgery Versus Surgery With Whole-Brain Radiation Therapy in Patients With One to Four Brain Metastases (JCOG0504): A Phase III, Noninferiority, Randomized Controlled Trial

Purpose Whereas whole-brain radiotherapy (WBRT) has been the standard treatment of brain metastases (BMs), stereotactic radiosurgery (SRS) is increasingly preferred to avoid cognitive dysfunction; however, it has not been clearly determined whether treatment with SRS is as effective as that with WBRT or WBRT plus SRS. We thus assessed the noninferiority of salvage SRS to WBRT in patients with BMs. Patients and Methods Patients age 20 to 79 years old with performance status scores of 0 to 2-and 3 if caused only by neurologic deficits-and with four or fewer surgically resected BMs with only one lesion > 3 cm in diameter were eligible. Patients were randomly assigned to WBRT or salvage SRS arms within 21 days of surgery. The primary end point was overall survival. A one-sided α of .05 was used. Results Between January 2006 and May 2014, 137 and 134 patients were enrolled in the WBRT and salvage SRS arms, respectively. Median overall survival was 15.6 months in both arms (hazard ratio, 1.05; 90% CI, 0.83 to 1.33; one-sided P for noninferiority = .027). Median intracranial progression-free survival of patients in the WBRT arm (10.4 months) was longer than that of patients in the salvage SRS arm (4.0 months). The proportions of patients whose Mini-Mental Status Examination and performance status scores that did not worsen at 12 months were similar in both arms; however, 16.4% of patients in the WBRT arm experienced grade 2 to 4 cognitive dysfunction after 91 days postenrollment, whereas only 7.7% of those in the SRS arm did ( P = .048). Conclusion Salvage SRS is noninferior to WBRT and can be established as a standard therapy for patients with four or fewer BMs.

Tamoxifen plus tegafur-uracil (TUFT) versus tamoxifen plus Adriamycin (doxorubicin) and cyclophosphamide (ACT) as adjuvant therapy to treat node-positive premenopausal breast cancer (PreMBC): results of Japan Clinical Oncology Group Study 9404.

PurposeA prospective randomized clinical trial was conducted to evaluate the efficacy of tamoxifen plus doxorubicin and cyclophosphamide compared to tamoxifen plus tegafur-uracil as an adjuvant therapy to treat node-positive premenopausal breast cancer (PreMBC).MethodsEligibility criteria included pathologically node-positive (n = 1–9) preMBC with curative resection, in stages I–IIIA. Patients were randomized to receive either tamoxifen 20 mg/day plus tegafur-uracil 400 mg/day (TU) for 2 years or six courses of a 28-day cycle of doxorubicin 40 mg/m2 plus cyclophosphamide 500 mg/m2 on day 1 along with tamoxifen (ACT) given for 2 years as adjuvant therapy. Primary endpoint was overall survival (OS), and secondary endpoint was recurrence-free survival (RFS).ResultsIn total, 169 patients were recruited (TU arm 87, ACT arm 82) between October 1994 and September 1999. The HR for OS was 0.76 (95 % CI 0.35, 1.66, log-rank p = 0.49) and that for RFS was 0.77 (95 % CI 0.44, 1.36, log-rank p = 0.37), with ACT resulting in a better HR. The 5-year OS was 79.7 % for patients in the TU arm and 83 % for those in the ACT arm. The 5-year RFS was 66.1 % for patients in the TU arm and 70.6 % for those in the ACT arm. A higher proportion of patients in the ACT arm experienced grade 3 leucopenia (0 % in the TU arm, 4 % in the ACT arm).ConclusionsThere were no significant differences in the efficacy of TU and ACT as adjuvant therapy.

Final Analysis, Cytogenetics, Long-Term Treatment, and Long-Term Survival In MM-003, A Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM)

Final Analysis, Cytogenetics, Long-Term Treatment, and Long-Term Survival In MM-003, A Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM)

SCALOP: Results of a randomized phase II study of induction chemotherapy followed by gemcitabine (G) or capecitabine (Cap) based chemoradiation (CRT) in locally advanced pancreatic cancer (LANPC).

LBA146 Background: CRT with G or 5FU (F) is used to treat LAPC. No multicenter, randomized studies have compared G-CRT vs. F-CRT or the oral fluropyrimidine, Cap-CRT. In the UK, where chemotherapy is traditionally standard of care for LAPC, a trial was conducted to assess the safety, efficacy, and deliverability of G-CRT and Cap-CRT. Methods: Eligibility: histologically proven inoperable LAPC < 7 cm in diameter. Induction chemotherapy: 3 cycles of GEMCAP (G 1,000 mg/m2 days 1, 8, 15; Cap 830 mg/m2 days 1-21 q28 days). Patients with stable/responding disease, tumor diameter ≤ 6cm, and PS 0-1 were eligible for CRT randomisation where patients received a further cycle of GEMCAP followed by either Cap (830 mg/m2 bd weekdays only) or G (300 mg/m2 weekly) with radiation (50.4 Gy/28 fractions). Treatment volume = tumour plus enlarged nodes and margins of 2 cm sup-inf and 1.5 cm radially. Prospective RT quality assurance was mandated. Primary end-point was 9-month PFS (Fleming’s design). Funder: Cancer Research UK (CR UK 07/040). Results: Between July 2009 and October 2011, 114 patients from 28 UK centres were registered of whom 74 patients were randomised. Randomised patient characteristics: median age 64.6; 55.4% male; WHO PS (0:1) 41.9%:58.1%; median tumor diameter 4cm; site (head:body) 85.1%:14.9%. During CRT, more patients in the G arm experienced grade 3/4 haematological (18.4% vs 0%, p=0.007) and non-haematological (26.3% vs 11.1%, p=0.095) toxicity. Both C and G arms passed the primary endpoint with 9-month PFS of 62.9% (80% CIs: 50.6%-73.9%) and 51.4% (80% CIs: 39.4%-63.4%) respectively. OS was significantly superior in the Cap-CRT arm (median OS 15.2 vs 13.4 months, HR=0.50, log rank p=0.025). Conclusions: SCALOP is the largest RCT comparing radio-sensitizers in pancreatic cancer and demonstrates that both G-CRT and Cap-CRT can be delivered safely and effectively. Both regimens met the pre-specified PFS criteria. Compared to G-CRT, Cap-CRT demonstrated significantly better survival and toxicity and should form the template regimen for future trials investigating RT dose escalation and combination with novel radio-sensitizers. Clinical trial information: NCT01032057.

Abstract B17: Phase I prevention study of atorvastatin in women at increased risk for breast cancer

Abstract Background: Currently FDA approved chemopreventive agents for breast cancer risk reduction include the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifen. However, acceptance amongst high risk women is low due to side effects that include thromboembolic events, uterine cancer and menopausal symptoms. Furthermore, SERMs only reduce the incidence of estrogen receptor (ER) negative breast cancer. Therefore, agents with a favorable toxicity profile that reduce incidence of ER negative and ER positive breast cancer are urgently needed. Atorvastatin is a statin that inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMGcoA) reductase. Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. In animal models, statins have been shown to be also effective against ER negative breast cancer. The aim of this study was to evaluate atorvastatin's potential chemopreventive effect by first demonstrating changes in breast cancer risk biomarkers in women at increased risk for breast cancer. Methods: High risk patients were randomized 1:1:1:1 to daily 10mg, 20mg, or 40mg Atorvastatin for 3 months, or to no treatment. High risk was defined as having a previous history of ductal carcinoma insitu (DCIS), lobular carcinoma insitu (LCIS), or atypical hyperplasia, or life time breast cancer risk greater than 20% by models including Gail, Claus, Tyrer-Cuzick, Boadicea, or BRCAPRO. All patients underwent baseline and 3 months blood collection and fine needle aspiration (FNA) of the breast for analysis of modulation in biomarkers. Biomarkers to be examined included in the blood: CRP, lipid profile, levels of atorvastatin, HMGcoA genotype and in breast FNA samples: Cytology, Ki 67, EGFR, bcl-2, CC3, and LXR evaluated by immunohistochemistry. Results: Between 2008 and 2012, 66 high risk women were randomized and 60 completed the study. Mean age was 51.8 years (range 27-69). One patient in the 20 mg arm experienced grade 3 toxicity (myalgia) that was not study drug related; 5 patients in the control arm, 6 in the 10mg, 9 in the 20mg and 4 in the 40 mg arm experienced grade 2 toxicity; only minority of them related to the study drug (arthraligia, myalgia, skin rash); 2 patients in the control arm, 3 in the 10 mg, 4 in the 20mg and 12 in the 40mg arm experienced grade 1 toxicity; only 10% of them possibly related to the study drug (arthralgia, myalgia, diarrhea, skin rash). Conclusion: Compliance during our atorvastatin phase I biomarker modulation study was very good. Atorvastatin was well tolerated with minority of the patients experiencing side effects, most of which were not related to the study drug. Biomarker analysis is ongoing and will be presented. This study was supported by the NCI N01CN35159 award. Citation Format: Banu Arun, Yun Gong, Diane Liu, Jennifer Litton, Angelica Gutierrez-Barrera, Blessy Sajan, Jack j. Lee, Lana A. Vornik, Terri Cornelison, Gabriel N. Hortobagyi, Scott Lippman, Powel H. Brown, nour Sneige. Phase I prevention study of atorvastatin in women at increased risk for breast cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B17.

The Addition of Rituximab to Fludarabine and Cyclophosphamide (FC) Improves Overall Survival in Newly Diagnosed Mantle Cell Lymphoma (MCL): Results of the Randomised UK National Cancer Research Institute (NCRI) Trial

Abstract 440▪▪This icon denotes a clinically relevant abstract Background:Rituximab is widely used in combination with chemotherapy for treating B cell lympho-proliferative disorders. In MCL, two randomised trials explored the addition of Rituximab to standard initial therapy. Neither demonstrated a significant improvement in either PFS or OS. In 2002 the NCRN initiated a phase II randomised trial of FC chemotherapy with or without Rituximab to evaluate response rates. In 2006 this was extended to a phase III study with overall survival as the primary end point. Trial:Newly diagnosed patients with MCL requiring therapy received up to 8 cycles of oral FC (Fludarabine 40mg/m2 and Cyclophosphamide 250mg/m2 both daily × 3) given every 4 weeks with a randomisation to the addition of Rituximab 375mg/m2 on day 1. There was no age limit to the study, no risk stratification and no consolidation of responses with transplantation or maintenance therapy. Results:370 patients were randomised. Median age was 66 years (range 36 – 88) with 76% male patients. The arms were well balanced by Mantle Cell International Prognostic Index (MIPI); 77% in the FCR arm and 71% in the FC arm were in the intermediate or high risk groups. 78% and 72% respectively received 4 or more cycles of FCR/FC. At the end of treatment the ORR was 90.6% in the FCR arm and 79.8% in the FC arm (p = 0.01) with CR + CRu rates of 64.7% and 46.9% (p = 0.002) respectively. 5.8% of patients in the FCR arm and 11.9% in the FC arm had PD at the end of treatment. Patients in the FCR arm had longer progression free and overall survival with HRs of 0.56 (95% CI: 0.43–0.73, p < 0.001) and 0.72 (95% CI: 0.54–0.97, p = 0.03) respectively. At a median follow up of 38.8 months the median PFS is 30.6 months in the FCR arm and 16.1 months in the FC arm. The median OS is 45.7 months for FCR and 37 months for FC. The major toxicities were haematological. Significantly more patients in the FCR arm experienced grade 3 or 4 Leucopoenia and Thrombocytopenia however the numbers of grade 4 were not significantly different. Combined grade III/IV toxicity showed 23.3% thrombocytopenia, 45.8% leucopoenia, 12.9% anaemia and 51.4% neutropenia. 11.8% of patients had significant infections. Renal toxicity was modest. 1 patient experienced grade III but there was no grade IV toxicity.Lymphoma was the commonest cause of death, but 29% of patients in the FCR arm and 24% in the FC arm died of other causes, of which almost half were infection related. An additional 11 patients died of a second malignancy, 4 of whom had AML. 14% of patients in the FCR arm and 10% in the FC arm died without evidence of disease progression. Conclusion:The addition of Rituximab to FC chemotherapy leads to a significant improvement in both PFS and OS with an acceptable level of additional toxicity. A significant number of patients treated with FC based chemotherapy die whilst in remission of non lymphoma related causes. [Display omitted] [Display omitted] Disclosures:Rule:Roche: Consultancy, Research Funding. Off Label Use: Rituximab in mantle cell lymphoma. Follows:Roche: Consultancy, Honoraria. Hillmen:Roche Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKine: Honoraria, Speakers Bureau; Genzyme: Research Funding; MundiPharma: Honoraria, Speakers Bureau. Walewski:Janssen-Cilag: ; Hoffman La Roche: Honoraria, Institutional/personal grants, travel/accommodation expenses; Mundipharma: Honoraria; Celgene: Honoraria.

A Phase I Pharmacologic Study of Necitumumab (IMC-11F8), a Fully Human IgG1 Monoclonal Antibody Directed Against EGFR in Patients with Advanced Solid Malignancies

This study aimed to determine a maximum tolerated dose (MTD) and recommended dose for disease-directed studies of necitumumab (IMC-11F8), a fully human IgG(1) monoclonal antibody directed at the epidermal growth factor receptor, and to characterize the safety profile, pharmacokinetics, preliminary antitumor activity, and immunogenicity of necitumumab. Patients with advanced solid malignancies were treated with 100 to 1,000 mg (flat dosing) necitumumab followed by a 2-week pharmacokinetics sampling period, before beginning 6-week cycles of therapy. Sixty patients received necitumumab weekly (29 patients) or every other week (31 patients). Two patients receiving 1,000 mg every 2 weeks experienced dose-limiting toxicities (DLT; grade 3 headache), accompanied by grade 3 nausea and vomiting in one patient. Occurring hours after the initial dose, these DLTs established 800 mg as the MTD. Mild dose-related skin toxicity was the most common drug-related toxicity (80%). One patient in each arm experienced grade 3 acneform rash, which responded to oral antibiotics and topical therapy. Toxicity was similar on both schedules. Necitumumab exhibited saturable elimination and nonlinear pharmacokinetics. At 800 mg (both arms), its half-life was approximately 7 days. All patients treated with >or=600 mg necitumumab achieved target trough concentrations (>or=40 microg/mL). Antibodies against necitumumab were not detected. Partial response and stable disease were experienced by 2 and 16 patients, respectively. Well tolerated, necitumumab is associated with preliminary evidence of antitumor activity, and achieves biologically relevant concentrations throughout the dosing period. The recommended dose of necitumumab for further clinical development is 800 mg (flat dose) weekly or every 2 weeks based on the clinical setting.

Randomized Trial of Postoperative Reirradiation Combined With Chemotherapy After Salvage Surgery Compared With Salvage Surgery Alone in Head and Neck Carcinoma

Full-dose reirradiation combined with chemotherapy has been shown to be feasible after salvage surgery with acceptable toxicity. The Groupe d'Etude des Tumeurs de la Tête et du Cou and Groupe d'Oncologie Radiothérapie Tête Et Cou groups performed a randomized study to assess its efficacy. Between 1999 and 2005, 130 patients with head and neck cancer were treated with salvage surgery and randomly assigned to full-dose reirradiation combined with chemotherapy (RT arm) or to observation (a "wait and see" approach; WS arm). Eligibility criteria were recurrence or a second primary tumor in a previously irradiated area, no major sequelae resulting from the first radiotherapy, good general condition, no distant metastasis, and salvage surgery with macroscopic complete resection. Patients in the RT arm received 60 Gy over 11 weeks combined with concomitant fluorouracil and hydroxyurea. Sixty-five patients were randomly assigned to each arm. There was no imbalance in the distribution of the main tumor and patients characteristics. The most serious acute toxicity in the RT arm was mucositis, attaining grade 3 or 4 in 28% of patients. At 2 years, 39% of patients in the RT arm and 10% in the WS arm experienced grade 3 or 4 late toxicity according to Radiation Therapy Oncology Group criteria (P = .06). Disease-free survival (DFS) was significantly improved in the RT arm, with a hazard ratio of 1.68 (95% CI, 1.13 to 2.50; P = .01), but overall survival (OS) was not statistically different. Full-dose reirradiation combined with chemotherapy after salvage surgery significantly improved DFS, but had no significant impact on OS. An increase in both acute and late toxicity was observed.

Pemetrexed + carboplatin versus gemcitabine + carboplatin in the treatment of stage IIIB/IV non-small cell lung cancer

7517 Background: A prospective, randomized, multicentre study was conducted to compare pemetrexed + carboplatin (PC) with a standard regimen, gemcitabine + carboplatin (GC). Methods: Chemonaive patients with verified non-small cell lung cancer, stage IIIB (ineligible for curative radiotherapy) or stage IV, WHO performance status (PS) 0–2, adequate hematology and creatinine-clearance &gt; 45 ml/min were eligible. All patients were supplemented with folic acid 0.4 mg OD and vitamin B12 1 mg IM every 9 weeks, from &gt;= 5 days before and through the treatment period. Patients were randomized to receive either pemetrexed 500 mg/m2 + carboplatin AUC=5 (Calvert) day 1 or gemcitabine 1,000 mg/m2 day 1 &amp; 8 + carboplatin AUC=5 (Calvert) day 1. Maximum 4 courses every 3 weeks were given. Primary endpoints: QoL defined as global health status, nausea/vomiting, dyspnea and fatigue - measured by the EORTC QLQ-C30 and LC13 before every cycle and 3 &amp; 11 weeks after the last cycle. Secondary endpoints: Overall survival (OS) and toxicity measured by the CTCAE v3.0. Stratification was done for age (−75 vs +75 years), stage (IIIB vs IV) and PS (0–1 vs 2). 190 evaluable patients in each arm were required to detect a 15% improvement on predefined QoL parameters with an a of 0.05 and β of 0.80. A 15% loss to follow up was expected. Results: 446 patients were included from Apr 05 - Jul 06. The two arms were well balanced with respect to age, sex, stage, PS and histological classification. 436 patients were eligible for the primary QoL-analyses. No statistical significant differences in mean score of the QoL-scales were observed between the arms. So far, 384 patients have been analysed for toxicity. Significantly more patients in the GC arm experienced grade 3–4 thrombocytopenia (48 vs 107, p&lt;0.001), leucopenia (44 vs 89, p&lt;0.001) and granulocytopenia (78 vs 98, p=0.02). No difference in the frequency of neutropenic fever was recorded. More patients in the GC arm received transfusion of platelets (5 vs 19, p=0.02). At present, 291 patients are deceased. We expect to present complete OS analyses for a minimum of 380 patients at the annual meeting. Conclusions: No differences were detected between the two arms with respect to the primary QoL outcome. Patients in the PC arm experienced less toxicity. No significant financial relationships to disclose.

Adaptive randomized study of idarubicin and cytarabine alone or with interleukin-11 as induction therapy in patients aged 50 or above with acute myeloid leukemia or high-risk myelodysplastic syndromes

A higher complete remission (CR) rate was observed in patients with acute myeloid leukemia (AML) who, on a prior randomized study of induction therapy, received gemtuzumab ozogamicin (GO) plus interleukin-11 (IL-11) rather than GO alone. An adaptive randomized phase III study of the addition of IL-11 to idarubicin and cytarabine (IA) induction in 100 patients ≥50 years of age with AML or high-risk myelodysplastic syndrome (MDS) was conducted. Median patient age was 67 years (range 50–82). Twenty-four of the 45 (53%) patients randomized to IA plus IL-11 achieved CR. Eight (33%) subsequently relapsed, 4 (17%) died in CR; median time to treatment failure (TTF) was 37 weeks. Twenty-nine of the 55 (53%) patients treated without IL-11 achieved CR. Eight (28%) subsequently relapsed, 2 (7%) died in CR; median TTF was 46 weeks. Median overall survivals were 21 and 59 weeks for the IA plus IL-11 and IA cohorts, respectively ( p = 0.271, log rank test; 0.435, Gehan–Breslow test). Ten episodes of the following grade 3 or 4 cardiopulmonary toxicities were observed in patients receiving IA plus IL-11, 12 such episodes in those receiving IA alone: atrial fibrillation, pleural effusions, myocardial infarction, bradycardia or hypotension. Two patients in each arm experienced grade 3 peripheral edema. There was no significant difference in incidence of any grade 3 or 4 adverse event, including thrombocytopenia, between treatment arms. There was no significant impact on CR rates, TTF, survival, or toxicity of adding an IL-11 regimen to IA induction in patients ≥50 years of age with AML.

Radiotherapy or chemotherapy followed by radiotherapy with or without amifostine in locally advanced lung cancer

Radiotherapy (RT) or radiochemotherapy is the treatment of choice for patients with medically or technically inoperable non-small cell lung cancer (NSCLC) localized to the primary site and regional lymph nodes. Radiation-induced damage has been recognized as a major complication in thoracic RT. The use of concurrent chemoradiation has been associated with an increase in acute and late toxicity. Amifostine (Ethyol) is an effective cytoprotective agent and also may have a role in protecting healthy lung tissue during radiation treatment. The purpose of these 2 clinical trials was to investigate whether daily pretreatment with amifostine could reduce the incidence of esophagitis, and acute and late lung toxicity without affecting the antitumor efficacy of the treatment. The first was a phase III randomized trial of 146 patients with locally advanced lung cancer. All patients received conventional RT to a total of 55 to 60 Gy, and they were assigned randomly to pretreatment with 340 mg/m(2) of amifostine (A). Acute and late toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) grading system from grades 0 to 4. Ninety-seven patients were evaluated 2 months post-RT for the incidence of pneumonitis; 43% (23 of 53) of patients in the RT arm and 9% (9 of 44) in the A plus RT arm experienced grade > or = 2 pneumonitis (P <.001). Forty-nine percent (26 of 53) of patients in the RT arm and 16% (7/44) in the A plus RT arm showed changes that were representative of grade > or = 2 lung damage in the computed tomography (CT) scan. Fibrosis was present in 53% (19 of 36) of patients receiving RT versus 28% (9 of 32) in the A plus RT arm at 6 months (P < 0.05). The incidence of esophagitis grade > or = 2 during week 4 was 42% (31 of 73) in the RT arm versus 4% (3 of 73) in the A plus RT arm (P <.001). Among 97 patients evaluable for response 2 months after RT, complete or partial responses were present in 76% (40 of 53) of patients in the RT arm and 75% (33 of 44) in the A plus RT arm (P = 1.0). The second trial was a phase II randomized study of 45 patients with NSCLC. All patients had received platinum-based induction chemotherapy before being referred for conventional radiation treatment with or without A; a total dose of 55 to 60 Gy was administered at the primary site. Acute and late toxicities were evaluated and graded according the RTOG criteria from grades 0 to 4. Forty-five patients were evaluable for response 2 months after RT. Complete or partial responses were achieved in 78% (18 of 23) of patients in the RT arm and 82% (18 of 22) in the A plus RT arm (P =.278). By week 5, 74% (17 of 23) of patients in the RT group versus 36% (8 of 22) in the A plus RT group experienced grade > or = 2 esophagitis. (During the follow-up period, pulmonary toxicity was evaluated by CT scan.) Three months after RT, 65% (15/23) of patients in the RT group and 32% (7 of 22) in the A plus RT group presented with grade > or = 2 pneumonitis (P =.038). Amifostine reduces the incidence of acute and late radiation-induced toxicities.