Pamela Drullinsky

The Safety of Dose-Dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Trastuzumab in HER-2/neu Overexpressed/Amplified Breast Cancer

PURPOSE Dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) is superior to every 3-weekly AC followed by P. Given the demonstrated cardiac safety for trastuzumab (T) with conventionally scheduled AC followed by P, we tested the safety of dd AC followed by P with T. The primary end point was cardiac safety, and the secondary end points were time to recurrence and overall survival. METHODS Patients with HER-2/neu immunohistochemistry (IHC) 3+ or fluorescent in situ hybridization (FISH)-amplified breast cancer and baseline left ventricular ejection fraction (LVEF) of >or= 55% were enrolled, regardless of tumor size or nodal status. Treatment consisted of AC (60/600 mg/m(2)) x 4 followed by P (175 mg/m(2)) x 4 every 2-weekly with pegfilgrastim (6 mg on day 2) + T x1 year. LVEF by radionuclide scan was obtained at baseline, at months 2, 6, 9, and 18. RESULTS From January 2005 to November 2005, 70 patients were enrolled. The median age was 49 years (range, 27 to 72 years); median LVEF at baseline was 68% (range, 55% to 81%). At month 2 in 70 of 70 patients, the median LVEF was 67% (range, 58% to 79%); at month 6 in 67 of 70 patients, it was 66% (range, 52% to 75%); at month 9 in 68 of 70 patients, it was 65% (range, 50% to 75%); and at month 18 in 48 of 70 patients, it was 66% (range, 57% to 75%). As of December 1, 2007, the median follow-up was 28 months (range, 25 to 35 months). One patient (1%) experienced congestive heart failure (CHF). There were no cardiac deaths. CONCLUSION Dose-dense AC followed by P/T followed by T is feasible and is not likely to increase the incidence of cardiac events compared to established regimens.

Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma

This multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD. Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of 1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity. Twenty-nine patients completed 4 cycles of BV + AVD, and 25 patients BV + AVD + 30 Gy ISRT. No clinically significant noninfectious pneumonitis was observed. Serious adverse events (≥grade 3) were reported in 4 patients, including febrile neutropenia, peripheral neuropathy, and hypertension. After 2 and 4 cycles of BV + AVD, 90% (26 of 29) and 93% (27 or 29) of patients achieved a negative PET scan, respectively. Two patients with biopsy-proven primary refractory HL were treated off-study. All 25 patients who completed BV + AVD + ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, 84-102). Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients (≥90%) achieved negative interim PET scans after 2 and 4 cycles of BV + AVD. Excluding the 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk. This trial was registered at www.clinicaltrials.gov as #NCT01868451.

Abstract P5-18-20: Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with metastatic HER2-overexpressing metastatic breast cancer.

Background: Pertuzumab (P) is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab (H), disrupting HER2 dimerization and signaling. The CLEOPATRA phase III trial showed that HP + docetaxel in HER2+ metastatic breast cancer (MBC) prolonged progression-free survival (PFS) compared to placebo + H + docetaxel. We report preliminary results of a phase II study to evaluate the safety and efficacy of weekly paclitaxel with HP (THP). Methods: Patients (pts) with HER2+ MBC with 0–1 prior treatment (Rx) are eligible. Pts receive weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → flat dose 420mg). The primary endpoint is PFS at 6 months (mo). Secondary endpoints include response, safety (including cardiac events), and tolerability. Evaluable pts are those who have started study Rx and are assessed at 6 mo for PFS. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 6–1-12, 38 of the planned 69 pts were enrolled and 20 pts were evaluable at 6 mo. Median age is 52 years (range 32 to 72). A total of 11 pts (55%) previously received trastuzumab in the adjuvant or metastatic setting, and 8 pts (40%) were being treated in the second-line metastatic setting. Of the 20 evaluable pts, G 3/4 toxicities were sepsis (1 pt, 5%), cholecystitis (1 pt, 5%), fatigue (1 pt, 5%), skin ulceration (1 pt, 5%) and cystic macular degeneration (1 pt with prior prolonged Rx with paclitaxel, 5%). Common G 1/2 toxicities included alopecia (20 pts, 100%), peripheral neuropathy (20 pts, 100%), fatigue (18 pts, 90%), ALT/AST elevation (17 pts, 85%), diarrhea (15 pts, 75%), rash (13 pts, 65%), nail changes (10 pts, 50%), mucositis (9 pts, 45%), dry skin (8 pts, 40%), and nausea (8 pts, 40%). Median LVEF was 64% at baseline (range 50% to 69%), 60% at 3mo (range 50% to 73%), and 60% at 6mo (range 49% to 67%). There were no cardiac events. At 6 mo, 15/20 pts (75%) were progression-free (2 CR, 8 PR and 5 SD); 5 pts had progressed. The 6 mo PFS results for all 38 enrolled patients will be updated. Conclusions: Our single-center phase II study continues to accrue, with no clinically significant diarrhea or signal of increased cardiac toxicity to date. Pertuzumab was recently FDA-approved in combination with trastuzumab and docetaxel. If the estimate of safety and activity is similar to results with docetaxel in CLEOPATRA, this study will provide support for weekly paclitaxel as an alternative option in combination with trastuzumab and pertuzumab in this setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-20.

Phase I/II trial of vorinostat with rituximab, cyclophosphamide, etoposide and prednisone as palliative treatment for elderly patients with relapsed or refractory diffuse large B-cell lymphoma not eligible for autologous stem cell transplantation.

The standard treatment of relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) in frail elderly patients has not been established. A variation was made on rituximab (R), cyclophosphamide (C), etoposide (E), procarbazine and prednisone (P), substituting vorinostat (V) for procarbazine. Patients ≥aged 60 years with relapsed/refractory DLBCL, not candidates for autologous stem cell transplantation, were treated R‐CVEP [R 375 mg/m2 intravenously (IV), day 1; C 600 mg/m2 IV days 1, 8: E 70 mg/m2 IV day 1, 140 mg/m2 days 2, 3 orally (PO); V (300 vs. 400 mg) PO and P 60 mg/m2 PO days 1–10] every 28 d for six cycles. Quality of life (QoL) was assessed in addition to response. Thirty patients (median age 76 years, 69–88) were enrolled (one died before treatment). Maximum tolerated dose (MTD) for V was 300 mg. For 23 patients at MTD (six phase I + 17 phase II), two were discontinued for toxicity, one withdrew consent, eight achieved complete response (35%), five achieved partial response (22%) and seven progressed (25%). Median overall survival was 17·5 months. Median progression‐free survival was 9·2 months. Nine patients are alive. QoL declined during treatment but improved above baseline for patients who completed treatment. In conclusion, R‐CVEP was tolerated at MTD and produced durable responses with improved QoL.

PD09-08: Combined Inhibition of mTORC1 with Temsirolimus and HER2 with Neratinib: A Phase I/II Study in Patients with Metastatic HER2−Amplified or Triple-Negative Breast Cancer.

Background: Hyperactivation of the PI3K-AKT-mTOR pathway is a postulated mechanism of resistance to anti-HER2 therapies and has also been described in triple-negative breast tumors. In HER2−amplified (HER2+) laboratory models, inhibition of this pathway induces activation of upstream receptor tyrosine kinases such as HER3. In triple-negative breast cancer (TN), HER1 overexpression has been identified and models show sensitivity to combined HER1 and mTOR inhibition. We hypothesize that dual inhibition of the PI3K pathway, HER1/2, and induced HER3 may be highly effective in patients with HER2+ or TN breast cancer (BC). This phase I/II trial is designed to determine the tolerability and possible efficacy of the mTOR inhibitor temsirolimus (T) plus the HER1/2 inhibitor neratinib (N) in patients with trastuzumab-refractory, HER2+ or TN BC. We will also explore mutational activation of the PI3K pathway in trastuzumab-refractory tumors as it relates to response to the T-N combination. Methods: The phase I dose-escalation study evaluated T (flat dose IV weekly) plus N (240 mg oral daily) in patients with metastatic HER2+ or TN BC. Cycle length was 4 weeks. Phase I end points included definition of maximum tolerated dose (MTD) and response rate (RR) per RECIST. The phase II study has a Simon two-stage design and evaluates the HER2+ and TN patients separately. Phase II endpoints include progression free survival and duration of response. Response was evaluated radiographically every 8 weeks, toxicity assessed every 2 weeks. All patients underwent biopsy of metastatic disease for biomarker assessment. Activating mutations in PIK3CA were assayed using the Sequenom MassARRAY system. Expression of PTEN was assessed by immunohistochemistry utilizing a published scoring system. Results: The phase I study enrolled 8 HER2+ patients who received a median of 5 (1-13) cycles of therapy. All patients had received trastuzumab and a median of 5.5 (2-12) prior lines of therapy. Frequent treatment-related grade 2 events were: hyperglycemia (4/8), elevated CPK (3/8), diarrhea (2/8), and rash (2/8). Grade 3 diarrhea was the dose-limiting toxicity. Other grade 3 toxicity was hyperglycemia (1/8); hematologic toxicities were not observed. The MTD of temsirolimus with neratinib is 8 mg IV weekly. Six patients treated at MTD were evaluable for response; 4 patients had PR, 1 had SD for a RR of 67%. PI3K pathway activation, through PIK3CA mutational activation or PTEN loss, was identified in 4/6 tumors analyzed and did not preclude response to temsirolimus and neratinib. Updated results reflecting the phase II patients will be reported. Conclusions: Temsirolimus plus neratinib is active in trastuzumab-refractory HER2+ patients. The phase II study is ongoing and additional efficacy and safety data in both HER2−amplified and triple-negative breast cancer patients will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-08.

Bortezomib, liposomal doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective treatment for patients with newly diagnosed multiple myeloma with Internatinal Staging System stage II or III, or extramedullary disease

Abstract We evaluated sequential bortezomib, liposomal doxorubicin and dexamethasone (BDD) followed by thalidomide and dexamethasone (TD) if ≥ partial response (PR) or bortezomib and TD (BTD) if < PR in untreated patients with multiple myeloma with International Staging System stage II/III or extramedullary disease. Of the 42 patients enrolled, two-thirds had cytogenetic abnormalities including high-risk findings [del(13q) by karyotype, t(4;14), loss of p53 or gain 1q] in one-third. After the planned three cycles of BDD, the overall response rate (ORR) was 81% with 40% ≥ very good partial response (VGPR), including 26% near complete and complete responses (nCR/CR). After the additional two cycles of TD or BTD, ORR was 83% with 60% ≥ VGPR including 43% nCR/CR, indicating deeper responses following sequential therapy (p = 0.008). Two-thirds of patients who presented with significant renal impairment had improved renal function. All patients undergoing stem cell harvest had a successful collection. BDD followed by TD or BTD is effective initial therapy for this population with higher-risk myeloma and results in rapid disease control and a high response rate.

A Phase I Study of Ibrutinib in Combination with R-ICE in Patients with Relapsed or Primary Refractory DLBCL

In the postrituximab era, approximately half of the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response to standard salvage therapy, and are thus ineligible to proceed to autologous stem cell transplantation with curative intent. The Bruton tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, particularly of non-germinal center (non-GC) cell of origin. We conducted a single-center phase 1 study evaluating dose-escalated ibrutinib, in a 3-by-3 design, in combination with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in physiologically transplant-eligible rel/ref DLBCL patients. Twenty-one patients have been treated and are evaluable for toxicity with no dose-limiting toxicities observed through expansion with ibrutinib at 840 mg daily at dose level 3. Of the 20 patients evaluable for response, per modern International Conference on Malignant Lymphoma criteria, 11 patients achieved complete remission (CR) and 7 patients achieved partial remission for an overall response rate of 90%. All evaluable patients with non-GC DLBCL achieved a metabolic CR. Ibrutinib in combination with R-ICE demonstrates tolerability and efficacy in rel/ref DLBCL, particularly of non-GC phenotype. This treatment program warrants further investigation in later-phase studies. This trial was registered at www.clinicaltrials.gov as #NCT02219737.

Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).

134 Background: Pertuzumab (P) is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab (H), disrupting HER2 dimerization and signaling. The CLEOPATRA phase III trial showed that HP + docetaxel in HER2+ MBC prolonged progression-free survival (PFS) compared to placebo + H + docetaxel. We report preliminary results of a phase II study to evaluate the safety and efficacy of weekly paclitaxel (T) with HP (THP). METHODS Patients (pts) with HER2+ MBC with 0-1 prior treatment (Rx) are eligible. Pts receive weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → flat dose 420mg). The primary endpoint is PFS at 6 months (mo). Secondary endpoints include response, safety (including cardiac events), and tolerability. Evaluable pts are those who have started study Rx and are assessed at 6 mo for PFS. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. RESULTS As of 5-1-12, 33 of the planned 69 pts were enrolled; 16 were evaluable at 6 mo. Of the 16 pts, G 3/4 toxicities included sepsis (1pt, 6%), cholecystitis (1pt, 6%), fatigue (1pt, 6%), skin ulceration (1pt, 6%) and cystic macular degeneration (1 pt with prior prolonged Rx with paclitaxel, 6%). G 1/2 toxicities included alopecia (16 pts, 100%), fatigue (15 pts, 94%), ALT/AST elevation (14 pts, 88%), neuropathy (14 pts, 88%), diarrhea (12 pts, 75%), rash (9 pts, 56%), nail changes (8 pts, 50%), nausea (7 pts, 44%), mucositis (7 pts, 44%), and dry skin (6 pts, 38%). Median LVEF was 63% at baseline, 60% at 3 mo and 58% at 6 mo. There were no cardiac events. At 6 mo, 12/16 pts (75%) were progression-free (2 CR, 7 PR and 3 SD); 4 pts progressed. CONCLUSIONS Our single-center phase II study continues to accrue, with no significant diarrhea or signal of increased cardiac toxicity to date. If the estimate of activity is similar to results with docetaxel in CLEOPATRA, this will provide support for THP as an alternative option in this setting.

P1-17-08: A Phase II Trial of Ganetespib: Efficacy and Safety in Patients (pts) with Metastatic Breast Cancer (MBC).

Background: Heat shock protein 90 (Hsp90) is a molecular chaperone that maintains the stability of a number of key cellular oncoproteins (client proteins). When Hsp90 is inhibited, its client proteins undergo ubiquitination and degradation. HER2 is one of the most sensitive client proteins of Hsp90 and we have previously shown that tanespimycin, a geldanamycin-based Hsp90 inhibitor, is active in trastuzumab-refractory HER2+ MBC, with a RR of 22% and clinical benefit rate of 59%. Ganetespib is a synthetic, small molecule, IV administered, non-geldanamycin Hsp90 inhibitor which has broader inhibitory effects on oncoproteins with pre-clinical antitumor activity in more breast cancer (BC) subtypes, including triple negative breast cancer (TNBC). We therefore tested ganetespib in an unselected cohort of patients with advanced BC. Methods: Pts with locally advanced or MBC were treated with single agent ganetespib at 200mg/m2 once weekly for 3 weeks, on a 28 day cycle. The primary endpoint of the trial was overall response rate using RECIST 1.1. Pts with HER2+ BC were required to have received prior therapy with trastuzumab. No more than 3 lines of chemotherapy in the metastatic setting were permitted and there was no limit on prior lines of hormone therapy. Pts were evaluated for response after 2 cycles. The trial used a Simon two-stage design requiring at least 3 responses among the first 22 pts, to allow expansion to a total of 40 pts. Results: A total of 14 pts have been treated thus far with a median age of 45.3 years (36.6 to 59.1) and the following subtypes: 8 ER+/HER2+, 3 ER-/HER2+, 1 ER+/HER2− and 2 TNBC. Pts received a median of 1.84 cycles (0.33 to 4). The most common treatment-related AEs were Grade 1/2 and included the following: diarrhea (64%), fatigue (50%), nausea (35%), vomiting (14%), insomnia (14%) and hypersensitivity reactions (35%). The diarrhea had an early onset ( Conclusions: These data show activity for single agent ganetespib in different subtypes of breast cancer. Ganetespib was well tolerated, with expected gastrointestinal toxicity that was mild in nature and manageable in all patients. Accrual continues and we will present updated data at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-08.

Dose Dense Cyclophosphamide, Methotrexate, Fluorouracil is Feasible at 14-Day Intervals: A Pilot Study of Every-14-Day Dosing as Adjuvant Therapy for Breast Cancer

PURPOSE Cyclophosphamide/methotrexate/fluorouracil (CMF) is a proven adjuvant option for patients with early-stage breast cancer. Randomized trials with other regimens demonstrate that dose-dense (DD) scheduling can offer greater efficacy. We investigated the feasibility of administering CMF using a DD schedule. PATIENTS AND METHODS Thirty-eight patients with early-stage breast cancer were accrued from March 2008 through June 2008. They were treated every 14 days with C 600, M 40, F 600 (all mg/m2) with PEG-filgrastim (Neulasta®) support on day 2 of each cycle. The primary endpoint was tolerability using a Simons 2-stage optimal design. The design would effectively discriminate between true tolerability (as protocol-defined) rates of ≤ 60% and ≥ 80%. RESULTS The median age was 52-years-old (range, 38-78 years of age). Twenty-nine of the 38 patients completed 8 cycles of CMF at 14-day intervals. CONCLUSION Dose-dense adjuvant CMF is tolerable and feasible at 14-day intervals with PEG-filgrastim support.