Paclitaxel In Pts Research Articles

Abstract CT012: PARTNER Trial: Neoadjuvant olaparib in triple negative breast cancer (TNBC)

Abstract Background: TNBCs in patients (pts) who are germline BRCA wild type (gBRCAwt) may show homologous recombination deficiency and genomic instability, resulting in a BRCA-like phenotype. The PARTNER Trial tested olaparib in combination with neoadjuvant carboplatin and paclitaxel in pts with TNBC (gBRCAwt). Methods: Pts with TNBC diagnosed locally were confirmed centrally with immunohistochemistry for ER, PR, HER2 and EGFR, CK5/6 and AR to define basal-like TNBC, before entry to the PARTNER trial. Pts were gBRCAwt. Tumours were assessed for tumour infiltrating lymphocytes (TILs). Pts were randomised 1:1 to research (R) and control arms (C). Pts received neoadjuvant carboplatin AUC 5, day(d) 1, with paclitaxel 80mg/m2 d1, 8, 15, every (q) 3 weeks (w), x 4 cycles(cy), +/- olaparib 150mg bd, po, d3-14 q 3w. Then all pts had 3cy of anthracycline chemotherapy before surgery. Primary endpoint was pathological complete response (pCR), and secondary endpoints included event-free survival (EFS), and overall survival (OS). A total of 454 patients were needed to attest 90% power with 5% significance assuming pCR rate of 50% in C and 65% in R. Results: From Sept 2016 to Dec 2021, 559 pts with TNBC (gBRCAwt) were randomised at 29 UK centres. Data cut-off was 30/11/23 with median (med) follow-up of 38 months (m). There were 276 R and 264 C pts in the intention-to-treat population. Pt and tumour characteristics were balanced between the arms: med pt age 49 years; 95% ECOG 0; 36% previous oophorectomy or post-menopausal; 95% tumour size ≤50mm; TILS score ≥60% in 22%. In R, 88% received at least 80% of the planned olaparib dose. More than 90% of patients in both R and C received at least 80% of the planned carboplatin (R 96% and C 94%) and paclitaxel (R 100% and C 99%) doses.Of 543 pts, 141 (51.1%) in R and 140 (52.4%) in C had a pCR with a difference of -1.3% (95% CI -9.7% to 7.0%, p-value=0.753). Percentage of pts with pCR increased with increasing TILs; pCR rate was 32% with TILs 0-10%, increasing to 67% with TILs 90-100%. Estimated EFS at 36 months (m) was 80% in R and 79% in C (log-rank p>0.9); estimated OS at 36m was 90% in R and 87.2% in C (log-rank p=0.8). Estimated 36m EFS rate was 90.4% (95% CI, 86.4 to 94.5) in pts with pCR and 70% (95% CI, 64.2 to 76.2) in pts with non-pCR (HR=0.3, 95% CI 0.2 to 0.4; p < 0.001). Estimated 36m OS was 95.7% (95% CI, 93.0 to 98.5) in pts with pCR, and 83% (95% CI, 78 to 88.2) in pts with non-pCR (HR=0.2, 95% CI 0.1 to 0.3; p < 0.001). More events and deaths were observed in non-pCR pts compared to pCR pts regardless of the treatment received. Conclusions: Neo-adjuvant olaparib in the dose and schedule tested, in addition to carboplatin/taxol and anthracycline chemotherapy in basal-like TNBC in gBRCAwt patients, did not improve pCR rates, EFS or OS. Pts who achieved a pCR had significantly better EFS and OS than those with non-pCR. These results are in marked contrast to the significant benefit of olaparib in those with gBRCA mutations reported in parallel. Citation Format: Jean E. Abraham, Karen Pinilla, Louise Grybowicz, Alimu Dayimu, Nikolaos Demiris, Caron Harvey, Lynsey M. Drewett, Rebecca Lucey, Alexander Fulton, Anne N. Roberts, Joanna R. Worley, Anita Chhabra, Wendi Qian, Richard M. Hardy, Stephen Chan, Tamas Hickish, Devashish Tripathi, Ramachandran Venkitaraman, Mojca Persic, Shahzeena Aslam, Daniel Glassman, Sanjay Raj, Annabel Borley, Jeremy P. Braybrooke, Stephanie Sutherland, Emma Staples, Lucy C. Scott, Mark Davies, Cheryl A. Palmer, Margaret Moody, Mark J. Churn, Jacqueline C. Newby, Mukesh B. Mukesh, Amitabha Chakrabarti, Rebecca R. Roylance, Philip C. Schouten, Nicola Levitt, Karen McAdam, Anne C. Armstrong, Ellen R. Copson, Emma McMurtry, Marc Tischkowitz, Elena Provenzano, Helena Earl, PARTNER Trial Group. PARTNER Trial: Neoadjuvant olaparib in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT012.

Abstract PD5-05: Impact of anti-HER2 therapy alone and in association with weekly paclitaxel on the ovarian reserve of young women with HER2-positive early breast cancer: Biomarker analysis of the NeoALTTO trial

Abstract Background: Knowledge regarding risk of treatment-induced premature ovarian insufficiency (POI) is crucial for appropriate oncofertility counseling. While the gonadotoxicity of anthracycline- and cyclophosphamide-based chemotherapy (CT) in young breast cancer (BC) patients (pts) is well established, the impact of anti-HER2 agents remains largely unknown and limited conflicting evidence exists for taxanes. Anti-Mullerian hormone (AMH) is an established biomarker of ovarian reserve; its measurements during systemic therapies may aid in diagnosis and prediction of POI. The NeoALTTO trial represented a unique setting to explore the acute gonadotoxicity of anti-HER2 therapy alone and in combination with weekly paclitaxel in pts not previously exposed to any other potentially gonadotoxic anticancer treatment. Methods: NeoALTTO (NCT00553358) is a multicenter, open-label, randomized phase III neoadjuvant trial in HER2-positive early BC pts randomized to receive lapatinib (L), trastuzumab (T), or their combination (L+T) alone for 6 weeks followed by the addition of paclitaxel for 12 weeks before surgery.The present analysis included only premenopausal women aged ≤45 years with available frozen serum samples at baseline (i.e. before administering any anticancer treatment), at week 2 (i.e. “biological window” of anti-HER2 therapy alone) and/or at surgery (i.e. after completion of paclitaxel plus anti-HER2 therapy). Central AMH testing was performed at Erasme Hospital (Brussels, Belgium) with the Roche Elecsys® AMH Plus assay (LoD=0.010 ng/ml). AMH levels during anti-HER2 therapy alone and then combined with paclitaxel were assessed as a measure of treatment impact on ovarian reserve. The impact of different anti-HER2 agents (T and/or L), pts’ age and baseline AMH levels on treatment gonadotoxicity were also investigated. Results: The present analysis included 130 pts with a median age of 38 years (IQR: 33-42 years), of whom 86 (66.2%) were ≤40 years. At baseline, median AMH levels were 1.29 ng/mL (IQR 0.56 - 2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median value: 1.10 ng/mL, IQR 0.45 - 2.09 ng/mL, p<0.001; median cumulative decrease: -12.5%, IQR -37.6% - 12.4%). At surgery, there was a large significant decline in AMH levels (median value: 0.01 ng/mL, IQR 0.01 - 0.03 ng/mL, p<0.001; median cumulative decrease: -99.9%, IQR -100.0% - -98.7%). Type of anti-HER2 treatment (L vs. L vs. T+L) did not impact the results: there was no significant difference between treatment arms in degree of reduction in AMH levels at week 2 (p=0.763) or at surgery (p=0.700). Age and pre-treatment ovarian reserve had a major impact on treatment-induced gonadotoxicity risk, with a more profound decrease in AMH levels observed for older pts (p<0.001) and those with lower baseline AMH levels (p<0.001). Among pts aged <35 years, there was no significant difference in AMH levels between those with (n=7) or without (n=35) a subsequent pregnancy at baseline (p=0.316), week 2 (p=0.463) or at surgery (p=0.610). Conclusions: This biomarker analysis of the NeoALTTO trial showed for the first time the potential acute gonadal damage induced by anti-HER2 therapies alone and with the addition of weekly paclitaxel. We observed a small but significant reduction in AMH levels during T and/or L alone and then a profound reduction to almost undetectable levels following the addition of weekly paclitaxel, without differences by specific anti-HER2 regimen. Age and pre-treatment AMH levels strongly impacted gonadotoxicity risk. While this analysis is limited by lack of AMH measurement in longer term follow-up, findings have important implications for future research and oncofertility counseling of premenopausal women with HER2-positive BC. Citation Format: Matteo Lambertini, Marcello Ceppi, Richard A. Anderson, David A. Cameron, Marco Bruzzone, Maria Alice Franzoi, Claudia Massarotti, Sarra El-Abed, Yingbo Wang, Christophe Lecocq, Paolo Nuciforo, Rebecca Rolyance, Lajos Pusztai, Joohyuk Sohn, Jacopo Ligato, Maria Maddalena Latocca, Luca Arecco, Barbara Pistilli, Kathryn J. Ruddy, Alberto Ballestrero, Lucia Del Mastro, Fedro A. Peccatori, Ann H. Partridge, Cristina Saura, Michael Untch, Martine Piccart, Serena Di Cosimo, Evandro de Azambuja, Isabelle Demeestere. Impact of anti-HER2 therapy alone and in association with weekly paclitaxel on the ovarian reserve of young women with HER2-positive early breast cancer: Biomarker analysis of the NeoALTTO trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-05.

Contextualizing a single-arm trial of ceralasertib (cer) plus paclitaxel with real-world data (RWD) in patients (pts) with advanced melanoma previously treated with anti-PD-(L)1(PDx) therapies.

e21542 Background: Metastatic melanoma, especially in pts who do not respond to PDx therapy, is an area of high unmet need. Chemotherapy may be used but clinical efficacy is limited. A recent Phase I study (NCT02630199) showed that cer + paclitaxel had promising anti-tumor activity with durable responses in 34 melanoma pts after failing PDx therapy. Given the lack of published prospective clinical trial data in the post-PDx setting, RWD was used to contextualize the results of the trial. Methods: Adult pts (≥18 years) diagnosed with advanced melanoma between Jan2011-Jun2020, who received PDx therapy alone or in combination with anti-CTLA4, and also received chemotherapy immediately after the PDx line (chemo cohort) were selected from the nationwide US-based Flatiron Health EHR-derived de-identified database. A subgroup of pts who received taxane was also selected. Overall survival (OS) was assessed using Kaplan-Meier methods. Key covariates such as age, gender, LDH level, number of prior lines of therapy, presence of brain and liver metastases, and prior BRAF/MEK treatment, were adjusted using propensity score-based weighting approach. Cox regression models were used to obtain the effect estimates for OS comparing the trial arm against the RWD cohorts. Results: A cohort of 114 pts met the inclusion criteria, of which 69 received taxane. Compared with the trial arm, the RWD cohorts were older, contained more males, with higher proportions receiving prior BRAF/MEK inhibitors, with brain metastasis, and LDH≤ULN. Median OS was 7.4 months (mo) in the trial arm, compared to 5.6 (unadjusted) and 3.5 mo (adjusted) in the chemo cohort. Hazard ratio of 0.49 (95% CI: 0.29-0.83, trial vs. chemo) indicated significant benefits of the trial arm over the chemo cohort. Analyses using taxane subgroup showed similar findings. Conclusions: The RWD cohorts demonstrated poor outcomes for the pts receiving chemotherapy, in particular taxanes, confirming this is a population of unmet need. The results show the potential for improved outcomes using cer + paclitaxel in pts previously treated with PDx.[Table: see text]

A first-in-human study of mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose escalation results.

3015 Background: Mirzotamab clezutoclax (ABBV-155) is a first-in-class antibody drug conjugate comprised of a BCL-XL (B-cell lymphoma - extra long) inhibitor, solubilizing linker, and a monoclonal anti-B7H3 antibody. Methods: Patients (pts) with relapsed and/or refractory (R/R) solid tumors were administered mirzotamab clezutoclax with or without paclitaxel. Dose escalation of mirzotamab clezutoclax was guided by Bayesian continual reassessment. Primary outcomes were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Secondary outcomes: safety, pharmacokinetics, and overall response rate per RECIST v1.1. Results: As of November 6, 2020, 31 pts received mirzotamab clezutoclax monotherapy (monoTx) and 28 pts received combination therapy with paclitaxel (comboTx). Overall demographics: median age 62 years (range 25–79); 61% female; 86% white; 24% ECOG 0, 76% ECOG 1; 51% had > 3 prior systemic therapies. The median duration of mirzotamab clezutoclax exposure was 3 cycles (range 1–14) for monoTx and 5 cycles (range 1–14) for comboTx. There were no dose limiting toxicities (DLT) reported with monoTx. In comboTx, 2 pts experienced a DLT: Grade 4 neutrophil count decreased and Grade 3 lymphocyte count decreased considered related to paclitaxel. 97% of all pts had adverse events (AEs). The most common AEs (in ≥20% of pts) overall were fatigue (39%), nausea (25%), diarrhea and arthralgia (22% each), vomiting and hypokalemia (20% each). AEs in ≥5 pts related to mirzotamab cleuzutoclax were fatigue (27%), diarrhea (12%), and nausea (9%). Related Grade 3/4 AEs overall (in > 1 patient) included anemia, lymphocyte count decreased, fatigue, and diarrhea (3% each). One patient on monoTx experienced a fatal cardiac arrest. No fatal AEs occurred on comboTx. Responses were observed with comboTx as shown in the Table. Conclusions: Mirzotamab clezutoclax as monotherapy and with paclitaxel demonstrates a tolerable safety profile (MTD not reached) with anti-tumor activity in R/R solid tumors. Further investigation in prospectively-selected B7H3 positive tumors as monoTx in pts with R/R small cell lung cancer and with paclitaxel in pts with R/R breast cancer and docetaxel in pts with R/R non-small cell lung cancer in the dose expansion phase is ongoing. Clinical trial information: NCT03595059. [Table: see text]

A first-in-human study of AO-176, a highly differentiated anti-CD47 antibody, in patients with advanced solid tumors.

2516 Background: AO-176 is a humanized IgG2 antibody that specifically targets CD47. Expressed by multiple tumor types, CD47 binds to signal regulatory protein a (SIRPa) on phagocytes, including macrophages and dendritic cells. The CD47-SIRPa complex results in a “don’t eat me” signal that allows the tumor to escape removal by the innate immune system, disabling the generation of an adaptive immune response. The differentiated mechanisms of action of AO-176 include promotion of phagocytosis, direct tumor cell killing through programmed cell death type III and induction of damage associated molecular patterns/immunogenic cell death, preferentially binding to tumor cells vs. normal cells, and enhanced binding at an acidic pH as found in tumor microenvironments. AO-176 has negligible binding to RBCs. Methods: In a phase 1/2 first-in-human study (NCT03834948) of AO-176, pts with advanced solid tumors associated with high CD47 expression and an ECOG PS of 0-1 were enrolled into escalating dose cohorts of AO-176 given IV every 7 days. Objectives included evaluation of safety, dose-limiting toxicity (DLT) and recommended phase 2 dose (RP2D), antitumor activity, pharmacokinetic (PK) parameters and exploratory biomarkers. Results: As of 4 Jan 2021, 27 pts were enrolled (median age 64 years; 67% female; 67% ECOG PS 1; median [range] of 4 [1-7] prior therapies for metastatic disease). Dose levels of 1, 3, 10, 20 and 20 (using step-up dosing) mg/kg were evaluated in >250 infusions. Most common (>10%) treatment-related adverse events (TRAEs) of any grade were thrombocytopenia and infusion-related reaction (IRR) (33% each), anemia (22%) with no evidence of hemolysis, nausea (19%), and fatigue (15%). The only G3+ TRAE occurring in >10% of pts was asymptomatic, brief thrombocytopenia (22%). No platelet transfusions were given. DLTs included IRRs in 2 pts dosed at 20 mg/kg, and asymptomatic thrombocytopenia and a cerebrovascular accident in 1 pt each in the 20 mg/kg step-up cohort. The RP2D was 10 mg/kg. Implementation of additional pre-medication and a 6-hr infusion duration in cycle 1 eliminated subsequent IRRs. Dexamethasone tapering and shortening of the infusion duration to 2 hrs was successful in all pts after cycle 1. Interim PK analysis of AO-176 demonstrated consistent exposure with linear PK. The T1/2 was ̃5 days. One pt with endometrial carcinoma who had not responded to any of 4 prior systemic regimens had a confirmed PR and remains on study for >1 year. 7 pts had SD as a best response, with 2 pts (endometrial carcinoma, gastric cancer) on study for >6 mos. Conclusions: AO-176 is a well-tolerated, differentiated anti-CD47 therapeutic. Durable anti-tumor activity was observed. Evaluations of AO-176 in combination with paclitaxel in pts with select solid tumors (NCT03834948) and as a single-agent in pts with multiple myeloma (NCT04445701) are ongoing. Clinical trial information: NCT03834948.

The association of tissue tumor mutational burden (tTMB) using the Foundation Medicine genomic platform with efficacy of pembrolizumab versus paclitaxel in patients (pts) with gastric cancer (GC) from KEYNOTE-061.

4537 Background: KEYNOTE-061 (NCT02370498) was a randomized, open-label, phase 3 study of pembrolizumab vs paclitaxel in pts with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma with tumor progression after first-line therapy (N = 592). In this analysis, we evaluated tTMB using FoundationOne CDx (F1CDx; Foundation Medicine) in pts with gastric or GEJ cancer in KEYNOTE-061. Methods: In pts with evaluable F1CDx tTMB data (n = 204), we analyzed the association of tTMB with confirmed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) within each treatment arm using one-sided (pembrolizumab) and two-sided (paclitaxel) Wald test nominal P for logistic regression (ORR) and Cox proportional hazards regression (PFS; OS) adjusted for ECOG performance status; significance was prespecified at 0.05. The clinical utility of tTMB was assessed using the prespecified cutoff of 10 mut/Mb for F1CDx. Clinical data cutoff: Oct 26, 2017. Results: tTMB was positively associated with ORR ( P < 0.001; AUROC, 0.68), PFS ( P < 0.001), and OS ( P = 0.003) with pembrolizumab but not paclitaxel (ORR, P = 0.047; AUROC, 0.30; PFS, P = 0.605; OS, P = 0.084). Pt outcomes by tTMB cutoff are reported in the Table; prevalence of TMB ≥10 mut/Mb was 17%. In pts with microsatellite stable disease-only, HRs (95% CI) by treatment arm for OS by F1CDx cutoff were 0.40 (0.14-1.17) for tTMB ≥10 mut/Mb (n = 21) vs 0.97 (0.70-1.34) for tTMB <10 mut/Mb (n = 168). Conclusions: In this exploratory analysis from KEYNOTE-061, tTMB as determined by F1CDx demonstrated a positive association with clinical outcomes with pembrolizumab, but not paclitaxel, in pts with GC; these findings are consistent with those reported with whole exome sequencing. Pembrolizumab demonstrated an OS benefit vs paclitaxel in the subgroup with tTMB ≥10 mut/Mb, which remained when pts with microsatellite instability-high disease were excluded. Clinical trial information: NCT02370498 . [Table: see text]

Randomized phase II study of sapanisertib (SAP) + paclitaxel (PAC) versus PAC alone in patients (pts) with advanced, recurrent, or persistent endometrial cancer.

6087 Background: SAP (TAK-228, MLN0128) is a selective dual inhibitor of mammalian target of rapamycin complexes 1 and 2. In endometrial tumor xenograft models, SAP+PAC exhibited stronger antitumor efficacy than PAC alone. Methods: Female pts with histologic/cytologic diagnosis of endometrial cancer were randomized to receive SAP 4 mg by mouth (days [d] 2–4, 9–11, 16–18, 23–25) plus PAC 80 mg/m2 intravenously (d 1, 8, 15), or PAC alone, in 28-day cycles until unacceptable toxicity or disease progression. Randomization was stratified by histologic subtype, lines of prior chemotherapy (1 vs. 2), and prior taxane therapy. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR; ORR + stable disease), and safety. Additional treatment arms of SAP alone (weekly dosing) and SAP+TAK-117 were closed after futility analyses. Results: 180 pts were randomized to SAP+PAC (n=90) or PAC (n=90); 86 and 87 pts received SAP+PAC and PAC, respectively; 3 pts from each arm were ongoing on treatment at data cut (30 July 2019). Baseline characteristics were balanced between arms. After a median follow-up of 17.2 vs. 14.4 mos with SAP+PAC vs. PAC, median PFS was 5.6 mos vs. 3.7 mos (hazard ratio [HR] 0.82; 95% CI 0.58–1.15). In pts with endometrioid histology (n=116), median PFS was 5.7 mos with SAP+PAC vs 3.3 mos with PAC (HR 0.66; 95% CI 0.43–1.03). In pts with nonendometrioid histology (n=64), median PFS was 3.6 mos with SAP+PAC vs. 5.4 mos with PAC (HR 1.09; 95% CI 0.62–1.90). Median OS was 13.7 mos with SAP+PAC vs. 14.6 mos with PAC (HR 1.01; 95% CI 0.67–1.53). Confirmed ORR was 24% with SAP+PAC vs. 18% with PAC (endometrioid, 23% vs. 16%; nonendometrioid, 28% vs. 22%); CBR was 80% vs. 58% (endometrioid, 84% vs. 55%; nonendometrioid, 72% vs. 63%). Median number of cycles received was 5 (range 1–23) with SAP+PAC and 4 (range 1–37) with PAC. Rates of grade ≥3 treatment-emergent adverse events (TEAEs) were 90% with SAP+PAC vs. 54% with PAC; the most common included anemia (21% vs.12%), neutropenia (12% vs. 3%), fatigue (12% vs. 5%), hypophosphatemia (12% vs. 1%), and pulmonary embolism (11% vs. 3%). Conclusions: Median PFS was longer with SAP+PAC vs. PAC in pts with endometrial cancer but did not reach statistical significance. PFS was particularly longer in the endometrioid subtype but again was not significant, and further studies are warranted. Incidence of grade ≥3 TEAEs was higher with SAP+PAC vs. PAC, but SAP+PAC toxicity was manageable, with no new safety signals. Clinical trial information: NCT02725268.

A dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of mTORC1/2 inhibitor XP-105 (BI 860585) as monotherapy and in combination with exemestane or paclitaxel in patients (pts) with advanced solid tumors.

3127 Background: Resistance to mTORC1 inhibition may develop through feedback loop leading to upregulation of mTORC2. XP-105, also known as BI 860585, is a potent dual mTORC1/2 inhibitor designed to overcome such resistance. This Phase 1 trial (NCT01938846) was performed to determine the MTD and activity of XP-105 alone or in combination with exemestane or paclitaxel in pts with advanced solid tumors. Methods: A 3+3 escalation design was used; Pts received XP-105 (5–300 mg/day) monotherapy or (40–220 mg/day) combined with fixed-dose exemestane 25 mg/day, or 80–160 mg/day combined with paclitaxel 60 or 80 mg/m2/week. A reduction of pAKT/total AKT ratio was used as a PD marker of target inhibition. Results: 90 pts were treated (41 with monotherapy, 25 and 24 in combination with exemestane, or paclitaxel respectively). XP-105 MTD was defined as 220 mg daily for monotherapy, and 160mg daily with exemestane 25 mg/d or paclitaxel 80 mg/m2/week. In the monotherapy arm, stable disease (SD) was reported in 8 pts (20%), with a median duration of 11 months. In the exemestane combination arm, 4 (16%) partial responses (PR) were reported. In the paclitaxel combination arm, 1 complete response (CR) and 4 PRs were reported (OR rate 21%). Disease control rate (CR/PR/SD) was 20%, 28%, and 58% in the monotherapy, XP-105/exemestane, and XP-105/paclitaxel arms, respectively. A sustained reduction in pAKT/total AKT to < 50% of baseline levels was observed with XP-105 ≥120mg daily. Overall, XP-105 was well tolerated; in the XP-105/paclitaxel combination the most frequent drug-related AEs were diarrhea and fatigue (58.3% each), hyperglycaemia (54.2%), anaemia (50%). Grade ≥3 AEs were hyperglycaemia, fatigue, diarrhea, anaemia, leukopenia. No PK interaction was observed. Conclusions: The MTD for XP-105 monotherapy and in combination with exemestane or paclitaxel was defined as 220 mg and 160mg once daily, respectively. Combination regimens showed higher activity as compared to monotherapy with durable OR in about 20% of pts. The observed safety profile of XP-105 compared favorably to those reported from other mTOR inhibitors. Clinical trial information: NCT01938846.

Abstract CT041: Primary results from FAIRLANE (NCT02301988), a double-blind placebo (PBO)-controlled randomized phase II trial of neoadjuvant ipatasertib (IPAT) + paclitaxel (PAC) for early triple-negative breast cancer (eTNBC)

Abstract Purpose: This hypothesis-generating trial evaluated neoadjuvant IPAT + PAC for eTNBC. Methods: Patients (pts) with eTNBC, T ≥1.5 cm and N0-2 were randomized 1:1 to receive 12 wks of weekly PAC 80 mg/m² + either IPAT 400 mg or PBO d1-21 q28d before surgery. Investigators chose adjuvant therapy. Stratification factors were PTEN status (Targos IHC), nodal status and tumor size. Co-primary endpoints were pathologic complete response (pCR) rate (ypT0/TisN0) in the intent-to-treat (ITT) and PTEN-low (Ventana IHC) populations. Secondary endpoints included pCR rate in pts with PIK3CA/AKT1/PTEN-altered tumors (NGS; Foundation Medicine), pre-surgery clinical response rates by MRI and safety. Results: From Feb 2015 to Mar 2017, 151 pts were randomized. Most had T1/2 (87%) N0 (65%) tumors. At the final analysis (9 Nov 2017), 132 pts (87%) had completed surgery. In all 3 populations, rates of pCR, overall clinical response and complete response (CR) by MRI favored IPAT (Table). IPAT was associated with more grade ≥3 AEs (32% vs 16% with PBO), especially diarrhea (17% vs 1%). AEs leading to IPAT/PBO discontinuation (9% vs 3%) or dose reduction (16% vs 1%) or PAC interruption (20% vs 12%) were more common with IPAT but median PAC dose intensity was 100% (IQR 100-100%) in both arms. Incidences of neuropathy (57% vs 61%) and neutropenia (14% vs 13%) were similar with IPAT vs PBO. Conclusions: Adding IPAT to PAC for eTNBC showed a small non-significant increase in pCR rate. The anti-tumor effect of IPAT was most pronounced in biomarker-selected pts: CR rates were 32% vs 6% in pts with PTEN-low tumors and 39% vs 9% in PIK3CA/AKT1/PTEN-altered tumors. Safety was consistent with prior IPAT + PAC experience. Similar to LOTUS in metastatic TNBC, FAIRLANE results support further evaluation of IPAT + PAC in pts with PIK3CA/AKT1/PTEN-altered tumors. A comprehensive translational research program is ongoing. TableEndpointITTPTEN-low (by IHC)PIK3CA/AKT1/PTEN-altered (by NGS)IPAT + PACPBO + PACIPAT + PACPBO + PACIPAT + PACPBO + PACpCR rate (ypT0/TisN0)13/76 (17.1%)10/75 (13.3%)3/19 (15.8%)2/16 (12.5%)5/28 (17.9%)4/34 (11.8%)Difference (95% CI)3.8% (-9.0 to 16.5)3.3% (-25.5 to 32.1)6.1% (-15.0 to 27.2)Overall clinical response ratea by MRI51/76 (67.1%)42/75 (56.0%)14/19 (73.7%)8/16 (50.0%)19/28 (67.9%)18/34 (52.9%)Difference (95% CI)11.1% (-5.6 to 27.9)23.7% (-13.6 to 60.9)14.9% (-12.4% to 42.3%)CR rateb by MRI21/76 (27.6%)10/75 (13.3%)6/19 (31.6%)1/16 (6.3%)11/28 (39.3%)3/34 (8.8%)aUnconfirmed complete or partial response. bUnconfirmed complete response. Citation Format: Mafalda Oliveira, Cristina Saura, Isabel Calvo, Jay Andersen, José Luis Passos Coelho, Miguel Gil Gil, Begoña Bermejo, Debra A. Patt, Eva Ciruelos, Stina M. Singel, Daniel J. Maslyar, Matthew Wongchenko, Wai Y. Chan, Amy V. Kapp, Lorena de la Peña, José Baselga, Steven J. Isakoff. Primary results from FAIRLANE (NCT02301988), a double-blind placebo (PBO)-controlled randomized phase II trial of neoadjuvant ipatasertib (IPAT) + paclitaxel (PAC) for early triple-negative breast cancer (eTNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT041.

Abstract P1-16-03: An open-label, multicenter phase 1b trial of radium-223 + paclitaxel in cancer patients with bone metastases: Safety results from the breast cancer patient subgroup

Abstract Background: Taxanes have an established role in treating breast cancer (BC), and combination with radium-223 (Ra-223) may be an option in patients (pts) with bone metastases. Both therapies impact hematologic parameters, but myelosuppression risk in combination is unknown. A phase 1b trial (NCT02442063) in cancer pts with bone metastases studied Ra-223+paclitaxel (PTX) safety and mode of interaction regarding myelosuppression; BC subgroup safety results are presented. Methods: Eligible pts had a malignant solid tumor with ≥2 bone metastases and were PTX candidates. Treatment (tx) was 7 PTX cycles (90 mg/m2/wk IV per local standard of care, 3 wk on/1wk off) + 6 Ra-223 cycles (55 kBq/kg IV; 1 injection q4wk, starting at PTX cycle 2). Primary endpoint was % pts with neutropenia and thrombocytopenia during Ra-223+PTX (cycles 2, 3) vs PTX alone (cycle 1). A dose-exposure-response model describing time course of Ra-223+PTX–induced suppression of absolute neutrophil counts was used to evaluate Ra-223+PTX mode of interaction (additive or synergistic) in the total population. Results: 15/22 enrolled pts were treated (total population); 7 had BC (BC subgroup). Baseline characteristics of the 2 groups were similar; ECOG PS was better in BC pts (Table). Fewer BC pts had prior taxane therapy (29% vs 53%), but rates of ≥3 prior chemotherapy regimens were similar (43% vs 47%). BC pts, vs total population, had slightly longer median tx duration for Ra-223 (6 vs 5.5 cycles) and PTX (7 vs 6 cycles), and more pts who completed 6 Ra-223 doses (57% vs 47%). Tx discontinuation related to disease progression in 29% of BC pts vs 33% in total population. Table shows TEAEs. In the BC subgroup, all 7 pts completed cycle 3 and Gr 3 neutropenia rates were 43% in cycle 2 and 14% in cycle 3, vs 29% in cycle 1; there was no Gr 4 neutropenia or Gr 3/4 thrombocytopenia. In the total population, 13 pts completing cycle 3 were in the pharmacodynamics analysis. Their Gr 3 neutropenia rates were 31% in cycle 2 and 8% in cycle 3, vs 23% in cycle 1; there was no Gr 4 neutropenia or Gr 3/4 thrombocytopenia. Myelosuppression model for the total population showed an additive effect of Ra-223 to PTX-induced neutropenia, with an additional 10% average decrease in absolute neutrophil count vs PTX alone. BC subgroup modeling was not feasible due to small sample size. Total Population n=15BC Subgroup n=7Median age (range), y61(45-76)58(45-68)Tumor type, n (%) Breast7(47)7(100)Prostate4(27)0Bladder1(7)0Non-small cell lung1(7)0Other2(13)0ECOG score, n (%) 06(40)5(71)18(53)1(14)Prior taxane therapy, n (%)8(53)2(29)≥3 prior chemotherapy regimens, n (%)7(47)3(43)TEAEs, n (%) Gr 3/49(60)2(29)Serious6(40)2(29)Gr 3/4 TEAEs, n (%)* Neutrophil count decreased6(40)3(43)White blood cell count decreased4(27)2(29) TEAE=treatment-emergent adverse event.*In >15% of patients. Conclusions: Ra-223 was well tolerated when combined with PTX in pts with solid tumors and bone metastases. The BC subgroup vs total population had slightly higher hematologic AE rates, but fewer Gr 3/4 and serious TEAEs; more BC pts also completed study tx. The combination should be explored further in pts with bone metastases. Citation Format: Danson SJ, Perets R, Lopez J, Joensuu H, Peer A, Harris SJ, Souza F, Ploeger B, Pereira KMC, Geva R. An open-label, multicenter phase 1b trial of radium-223 + paclitaxel in cancer patients with bone metastases: Safety results from the breast cancer patient subgroup [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-16-03.

Role of different germline BRCA mutations in response to platinum-based chemotherapy in patients (pts) with triple-negative breast cancer (TNBC).

e13008Background: TNBC is associated with aggressive behavior and poor prognosis. TNBC is the most common subtype seen in patients with hereditary BRCA associated breast cancer. Because of defects of homologous recombination these tumours may be extremely sensitive to DNA-damaging agents such as platinum. Little is known about influence of different germline BRCA mutations on response to chemotherapy. Previously we have shown that somatic BRCA1 mutations may determine different responses to platinum-based chemotherapy. Now we analyse efficacy of dose-dense schedule of doxorubicin, cisplatin and paclitaxel in pts with hereditary BRCA associated TNBC. Methods: Twenty eightpts with early (cT1-2N0-1M0) and locally advanced (cT2-4N2-3M0) hereditary BRCA associated TNBC were treated with dose-dense combination of doxorubicin, cisplatin and paclitaxel followed by surgery. Mutations distribution is summarized in table 1. Pathological response was evaluated according to the Chevallier classification. Results: Medi...

Abstract OT1-03-18: COLET: A multistage, phase 2 study evaluating the safety and efficacy of cobimetinib in combination with paclitaxel as first-line treatment for patients with metastatic triple-negative breast cancer

Abstract Background: Cobimetinib (cobi) is a potent, highly selective inhibitor of MEK that has shown benefit when administered in combination with the BRAF inhibitor vemurafenib in BRAFV600-mutated metastatic melanoma. Preclinical data suggest that up-regulation of the MAPK pathway is a potential resistance mechanism against taxane chemotherapy. Clinically, the combination of MEK inhibition and taxane chemotherapy in non–small cell lung cancer patients (pts) has improved response rate (RR) and progression-free survival (PFS). Because most triple-negative breast cancer (TNBC) pts develop resistance to taxane chemotherapy and because genetic alterations (including mutations and gene amplifications) in the MAPK pathway are present in many TNBC tumors, the combination of taxane chemotherapy and MEK inhibition could be an effective treatment option. Study design: COLET (WO29497) is a multistage study designed to evaluate the safety of and to estimate the efficacy of cobi  paclitaxel in pts with metastatic or locally advanced TNBC who have not previously received systemic therapy for metastatic disease. The study will be conducted in 2 stages: an initial safety run-in stage of approximately 12 pts, followed by a randomized stage in which approximately 100 pts will be randomly assigned in a 1:1 ratio to receive either cobi + paclitaxel or placebo + paclitaxel. Pts will receive paclitaxel 80 mg/m2 on Days 1, 8, and 15 of each 28-day cycle and cobi/placebo 60 mg/day on Days 3-23 of each 28-day cycle until progression of disease or toxicity occurs. Key eligibility criteria: • Metastatic or locally advanced (not amenable to curative resection) TNBC • No prior systemic therapy for metastatic or unresectable locally advanced TNBC • Neoadjuvant or adjuvant chemotherapy or radiation therapy is allowed if completed >6 months before the start of study treatment • Measureable disease using Response Evaluation Criteria In Solid Tumors, version 1.1 (RECIST v1.1) • History of or active untreated or unstable brain metastases or requiring corticosteroids for brain metastases precludes eligibility • Left ventricular ejection fraction (LVEF) greater than the institutional lower limit of normal or above 50% Specific aims of the safety run-in stage: Determine the safety and tolerability of cobi when administered in combination with paclitaxel. Specific aims of the randomized stage: Investigator-assessed PFS (primary end point); safety; pharmacokinetics; the effect of intrinsic subtypes and genetic alterations in PFS; mechanisms of resistance; and health-related quality of life. Accrual: Approximately 112 pts from sites across Europe, North America, and the Asia-Pacific region. Statistical methods: In the randomized stage, pts will be followed up until a total of 60 PFS events occur across the 2 arms. This provides 77% power to detect a hazard ratio of 0.5 at a two-sided significance level of 0.05. Contact information: Registered with ClinicalTrials.gov, identifier NCT02322814. For more information, please contact Roche/Genentech trials, 888-662-6728 (US only) or reference study ID WO29479 at www.roche.com/about_roche/roche_worldwide.htm. Citation Format: Kim S-B, Miles D, Rhee J, Yan Y, Hsu J, Brufsky A. COLET: A multistage, phase 2 study evaluating the safety and efficacy of cobimetinib in combination with paclitaxel as first-line treatment for patients with metastatic triple-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-18.

Abstract P2-16-22: A dose-finding phase lb study of BEZ235 in combination with paclitaxel in patients with HER2-negative, locally advanced or metastatic breast cancer

Abstract Background: The PI3K/Akt/mTOR pathway is the most frequently activated signaling pathway in breast cancer (BC). Activation of this pathway promotes tumor growth and progression, and resistance to anticancer therapies, including paclitaxel (PTX). BEZ235 is an oral, ATP-competitive inhibitor that targets class l PI3K and downstream effectors mTORC1/2. BEZ235 has shown antiproliferative, proapoptotic, and antiangiogenic activity in multiple preclinical cancer models. In a Ph I study, single-agent BEZ235 given twice daily (BID) showed preliminary signs of clinical activity. Methods: This was a multicenter, open-label Ph Ib/II study of daily, oral BEZ235 given BID in combination with weekly (QW) intravenous PTX in women with HER2-, metastatic or locally advanced BC (NCT01495247). For the Ph Ib part, the primary objective was to determine the maximum tolerated dose (MTD)/recommended Ph II dose (RP2D) of BEZ235 in combination with PTX based on dose-limiting toxicities (DLTs) using a 5-parameter adaptive Bayesian logistic regression model with overdose control. MTD was defined as the highest dose not causing medically unacceptable DLTs in >35% of pts during Cycle 1 (28 days). Secondary objectives included safety, preliminary activity, and PK. Safety was monitored by physical exams, vital signs, laboratory tests, weight, and cardiac health. AEs were assessed continuously by CTCAE v4.03. Tumor evaluations were performed at screening and every 8 wks after starting treatment, and assessed locally by RECIST v1.1. Results: As of April 12, 2013, 18 pts (mean age: 50 yr; 67% ≥4 prior lines of antineoplastic therapy) had been enrolled into Ph Ib. 13 pts received BEZ235 200 mg BID + PTX 80 mg/m2 QW. The dose level was then reduced to BEZ235 100 mg BID + PTX 80 mg/m2 QW (n = 5). Of 17 evaluable pts (12 at the 200-mg BID dose; 5 at the 100-mg BID dose), 6 (35%) developed ≥1 DLTs (5 [42%] at the 200-mg BID dose; 1 [20%] at the 100-mg BID dose): neutropenia (n = 3 [1 at the 100-mg BID dose]), stomatitis (n = 3), nausea (n = 2), and vomiting (n = 1). Of 18 pts, 12 have discontinued (6 due to disease progression; 4 AEs; 1 physician decision; 1 pt/guardian decision). Median duration of exposure to BEZ235 and PTX was 76 days each. The most common suspected study drug-related AEs included asthenia (78%), nausea (72%), neutropenia (72%), diarrhea (67%), stomatitis (61%), and decreased appetite (56%). Among 13 pts receiving BEZ235 200 mg BID, 2 (15%) achieved a PR, 4 (31%) had SD, and 4 (31%) had PD; all 5 pts receiving BEZ235 100 mg BID had SD. PK results showed large interpatient variability at both dose levels. Analysis of pAKT and p4EBP1 was performed on peripheral blood mononuclear cells collected from pts before treatment and 4 h following treatment (Cmax). PK/PD analysis did not provide evidence of a strong and consistent correlation between BEZ235 plasma concentrations and pAKT inhibition. Conclusions: The MTD/RP2D of BEZ235 in combination with PTX in pts with locally advanced or metastatic HER2- BC was not reached. Based on the observed overall safety profile, efficacy, variable PK, and PD data from the Ph Ib part of this study, further enrollment has stopped. The Ph II part of the study will not be conducted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-22.

SAMIT: Preliminary safety data from a 2x2 factorial randomized phase III trial to investigate weekly paclitaxel (PTX) followed by oral fluoropyrimidines (FPs) versus FPs alone as adjuvant chemotherapy in patients (pts) with gastric cancer.

4017 Background: Recently, S1 has become a standard adjuvant chemotherapy for localized gastric cancer in Japan with no comparison among FPs so far. PTX is one of key drugs in gastric cancer especially for those with peritoneal metastases, for which serosal invasion is a major risk. SAMIT is an ongoing randomised phase III trial of adjuvant FPs (S1 or UFT) ± PTX in pts with SE or SI gastric adenocarcinoma. Methods: Pts received either A: UFT 267 mg/m2/day for 4w, every 4w x6; B: S1 80 mg/m2/day for 2w, every 3w x 8; C: paclitaxel 80 mg/m2 Day 1, 8 for the first 3w x1, Day 1, 8, 15 every 4w x2, followed by UFT 267 mg/m2/day for 4w, every 4w x3; or D: paclitaxel as in C, followed by S1 80 mg/m2/day for 2w, every 3w x4. The duration of treatment was amended from 24w to 48w by prolonging the part of FPs according to the results of ACTS-GC in 2007. Primary endpoint is disease-free survival and total number of patients was calculated to be 1480 where 90% power for superiority of C+D group and non-inferiority of UFT with 88% power in the upper equivalence margin of 1.25. The Independent Data Monitoring Committee undertook a review of the first 976 pts at the first interim analysis, and we present the preliminary safety data. Results: Between August 2004 and September 2009, 1,538 pts were accrued from 232 institutes, and 1495 pts were randomized. The pts who required dose reduction or skip between the first to third courses were 32%, 33%, 22%, and 27%; in the fourth to sixth courses were 18%, 20%, 18%, and 28% for A, B, C, and D, respectively. The compliance of UFT or S1 between the fourth to sixth courses were 76%, 86%, 81%, and 85% for A, B, C, and D, respectively. Grade 3/4 hematological toxicities were 0.8%, 0.4%, 1.6%, and 3.4%; grade 3/4 non-hematological toxicities were 7.3%, 7.2%, 2.4%, and 8.9% for A, B, C, and D, respectively. There was no treatment-related death. Conclusions: Preliminary safety data indicate comparable compliance; different but acceptable rates of complications in the 4 arms. The second interim analysis is currently undertaken and the final results will be formally assessed in 2012.

Final results of a phase I study using oral temozolomide (TMZ) daily for 14 days with weekly paclitaxel in patients (pts) with advanced malignancies

12020 Background: TMZ is an alkylating agent with activity in a variety of neoplasms. The optimal schedule of administration for TMZ has not been established and only a few studies have studied it in combination with other agents. Repair of TMZ-induced DNA damage is associated with the activity of O-6 alkylguanine-DNA-alkyl transferase (AGT). Preclinical and clinical data indicate that prolonged exposure to TMZ results, not only in enhanced DNA alkylation, but also in depletion of AGT. This serves as the rationale to study TMZ using protracted schedules. Methods: The aim of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of oral TMZ given daily for 14 days with weekly paclitaxel in pts with advanced cancers. Forty-five pts received 136 cycles of TMZ at escalating doses (50, 75, 100, 125 and 150 mg/m2/day × 14 days) plus paclitaxel at 80 mg/m2 on days 1, 8, and 15. Pts were stratified as lightly (LP) or heavily (HP) pretreated and MTD defined as the dose level (DL) at which 1/6 patients developed DLT. Results: Twenty-four LP patients were treated at 5 DLs with all but one evaluable for toxicity. Febrile neutropenia and grade 3 thrombocytopenia were the DLTs. MTD in this group was the 125 mg/m2/day level. Twenty-six HP were treated at 5 DLs and 21 were evaluable for toxicity. Febrile neutropenia and grade 3 thrombocytopenia were the DLTs. MTD for this group was also 125 mg/m2/day. Thirty-eight (84%) pts were evaluable for response after 2 cycles of therapy. Three (8%) pts had a partial response (lung, lymphoma, ependymoma), 20 (53%) remained stable and 15 (39%) developed disease progression. Six (16%) pts remained stable for 6 cycles or more (2 sarcomas, 2 lung, 1 pancreas, 1 glioblastoma). Conclusions: We concluded that combining oral TMZ at a dose of 125 mg/m2/day for 14 days with standard-dose weekly paclitaxel is safe in both HP and LP pts. [Table: see text]

Paclitaxel (PTX) as second line treatment in patients (pts) with small cell lung cancer (SCLC) refractory to carboplatin - etoposide: A multicenter phase II study

7211 Background: pts non-responding to 1st line chemotherapy or relapsing within 3 months (m) of confirmed prior response are considered refractory to treatment and candidate for phase II trials, as second line therapy in refractory SCLC is disappointing (Huisman, 1999). The present study aimed to assess the activity and toxicity of single agent PTX in pts refractory to first line carboplatin and etoposide. Methods: Eligible pts had to present with cytological or histological proof of SCLC, at least 1 measurable lesion, WHO PS ≤ 2, age ≥ 18 years, and adequate renal, hepatic and bone marrow function. After informed consent, pts were treated in first line with carboplatin AUC 6 on d1 or 100 mg/m2 on d1–3 and etoposide 120 mg/m2 on d1–3, q 4w for up to 6 cycles Refractory pts were treated with PTX 200 mg/m2 as a 3 h infusion q 3w for up to 6 cycles, after adequate premedication. Appropriate dose reductions were made according to toxicity. The prophylactic use of CSF's was not allowed. PCI was optional and thoracic irradiation mandatory in LD pts obtaining response. Response and toxicity were defined using WHO and NCI-CTC criteria, respectively. The study was powered to detect a true response rate of PTX ≥ 20% using a 2 step design according to Gehan with a 2-sided alpha error of 0.05 and a beta error of 0.1. Results: between October 1998 and August 2001, 93 pts with the following characteristics started 1st line therapy: male 98%, median age 66 years (range 39–88), WHO PS 0/1/2: 18/75/7%, Extensive stage 55%. 44 refractory pts, of whom 52% non-responders to 1st line, received PTX. Mean number of PTX cycles was 3 (range 1–6). The ORR was 20% (95%CI 11–29%). Toxicity was evaluable in 40 pts:grade ¾ (%): fatigue 13/-, dyspnea 5/-, neuropathy 8/-, arthralgia/myalgia 8/-, anemia 5/-, febrile neutropenia: 23% . No toxic deaths were observed, although 3 pts died of disease progression during treatment. Median OS and TTP on PTX were 4 and 3 m, respectively. Conclusions: the observed activity of PTX in pts with refractory SCLC looks promising, provided febrile neutropenia can be avoided/prevented. No significant financial relationships to disclose.