Stella, Philip J.

Abstract Background: Although major advances have been made in the treatment of HER2+ metastatic breast cancer (MBC), the goal of care remains largely palliative, therefore better treatments are needed. Given encouraging preclinical and clinical data, the combination of cyclin dependent 4/6 kinase inhibitors and HER2-directed therapy is further being evaluated in this trial. Trial Design: In this phase I/II multicenter trial, we will determine the maximum tolerated dose (MTD) of abemaciclib (Abem) combined with T-DM1. Three Abem dose levels will be examined, 50 mg, 100 mg and 150 mg. The phase 2 portion of this trial will examine whether PFS is increased with addition of Abem to T-DM1 in two pt cohorts - those with ER+ HER2+ MBC and those with ER-HER2+ MBC. For phase 2, a pre-registration biopsy is required to confirm ER and HER2-status and to determine levels of tumor infiltrating lymphocytes; vimentin (an epithelial-mesenchymal transition marker); and CD8 and FOXP3 expression. Blood samples will be collected pretreatment , at 6 weeks, and at progression for all pts. Eligibility Criteria: Phase I&II: All pts must have HER2+ MBC per ASCO-CAP guidelines and prior treatment with a taxane, trastuzumab and pertuzumab. For the phase Iportion, pts can have measurable or non-measurable disease with no restriction on the number of prior lines of therapy. In the phase II portion, pts must have measurable disease with ≤1-2 prior lines of chemotherapy alone, ≤1 HER2-directed therapy alone, and/or chemotherapy with HER2-directed therapies. There is no limit on prior endocrine therapy. Specific Aims: The primary objective of the phase II trial is to assess whether addition of Abem to T-DM1 increases PFS in one or both patient cohorts. Secondary objectives include an assessment of toxicity, objective response rates and overall survival. Correlative studies will assess the association between baseline TIL levels, vimentin expression, and CD8/FOXP3 expression with PFS. Changes in peripheral blood mononuclear cells, CTCs, ctDNA and serum thymidine kinase 1 during the course of treatment will be examined to determine if there is a link with PFS outcomes overall and separately for each cohort. Pharmacogenomic studies will determine if pts with the FCGR3A-158 polymorphism derive less benefit from T-DM1 and have inferior PFS outcomes compared with pts who do not have this polymorphism. Statistical Methods:Phase I: Standard 3+3 design, with dose limiting toxicities as per protocol. Phase II: For each pt cohort, a stratified randomization scheme will be used to assign pts to treatment with liver mets as a stratification factor. For each pt cohort, a stratified log rank test will be used to assess whether PFS is increased with the addition of Abem to T-DM1. A non-binding futility analysis will be applied in each cohort after 58 events in the ER+ HER2+ MBC study cohort and 48 events in the ER- HER2+ MBC study cohort. Present Accrual: 0; target accrual: minimal 120 pts., maximal 140 pts CohortOne-sidedalphaPowerAccrual Period (accrual rate)Follow-up after close of enrollmentPFS with T-DM1PFS with abema and T-DM1Number of eligible patientsER+/HER2+0.100.912 months (5-6 pts per month)12 months12 weeks24 weeks64 (32 per arm)ER-/HER2+0.100.8512 months (3-4 pts per month)12 months6 weeks12 weeks50 (25 pts per arm) Citation Format: Ciara C O Sullivan, Jun He, Vera J Suman, Krishna R Kalari, Roberto A Leon-Ferre, Jose C Villasboas-Bisneto, Pratima Chalasani, Demet Gokalp Yasar, Daniel M Anderson, Philip J Stella, Anthony J Jaslowski, Susan H Tannenbaum, Angela Saverimuthu, Donald Northfelt, Alvaro Moreno-Aspitia, Jodi M Carter, Minetta C Liu, Liewei Wang, Zhenkun Lou, Matthew P Goetz. A phase I/II trial of abemaciclib and T-DM1 in women and men with HER2-positive advanced or metastatic breast cancer that has progressed on treatment with a taxane, trastuzumab and pertuzumab (THP) (ACCRU-BR-1801) [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 OT2-19-05.

Abstract Background Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. Patients and Methods In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46). Conclusion In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted. Clinical Trial Registration: NCT02292758

11095 Background: Biologic characterization of CTCs is increasingly important in determining metastatic breast cancer (MBC) patient (pt) prognosis and treatment prediction. Combined preliminary results from two earlier metastatic BC NCCTG trials, N0234 & N0336, suggested that the change in CTC mammaglobin (MGB1) gene expression between baseline and two cycles of chemotherapy predicted tumor response (p=0.04). The objectives of this study were to 1) determine CTC gene expression of CK19 and MGB1 before, during, and after treatment in N0436 & N0437 and 2) determine associations between baseline and post-treatment gene expression and treatment response. Methods: CTCs were enriched using CD45-depletion from ∼10ml EDTA blood obtained from metastatic BC pts before, after two cycles, and at end of treatment with either first/second-line irinotecan plus cetuximab (N0436) or first-line paclitaxel poliglumex and capecitabine (N0437). CK19 and MGB1 mRNA levels were determined using quantitative RT-PCR in baseline and serial CTC samples of up to 19 pts from N0436 and 40 pts from N0437. The relative gene expressions were normalized to β2-microglobulin and calibrated to healthy blood using the 2-ΔΔCt algorithm; a value of 2 was defined as positive for the respective marker. Results: CK19+ mRNA was detected in 58% of baseline samples from N0436 (11/19) and N0437 (23/40). MGB1+ mRNA was detected in 32% (6/19) and 38% (15/40) of N0436 and N0437 baseline samples, respectively. CK19+ mRNA was detected in 50% (7/14) and 56% (29/52) of N0436 and N0437 serial CTC samples, respectively. MGB1+ mRNA was detected in 29% (4/14) and 27% (14/52) of N0436 and N0437 serial CTC samples, respectively. Of the 66 serial samples, 27% of samples (18/66) had turned positive from baseline for CK19 or MGB1. CK19 mRNA was detected in 85% (33/39) of MGB1+ mRNA samples but their baseline mRNA levels were not correlated. Conclusions: CK19 mRNA was detected in MBC pts with similar frequencies to the CellSearch imaging system. CK19 was detected at a higher frequency than MGB1. In the majority of cases, MGB1 was co-expressed with CK19. Associations between gene expression and treatment response using Chi-Squared analyses and Cox regression models will be presented. No significant financial relationships to disclose.

9532 Background: Chemotherapy induced peripheral neuropathy (CIPN) continues to be a substantial problem for many cancer patients (pts). Pursuant to promising appearing pilot data, the current study evaluated the use of vitamin E for the prevention of CIPN. Methods: A phase III, randomized, double-blind, placebo controlled study was conducted in pts undergoing therapy with neurotoxic chemotherapy, utilizing twice daily dosing of vitamin E (400mg)/placebo. The primary endpoint was the incidence of grade 2+ sensory neuropathy (SN) toxicity (CTCAE v 3.0) in each treatment arm, analyzed by Chi-square testing. Major eligibility criteria included: planned curative intent adjuvant chemotherapy with neurotoxic chemotherapy, ≥ 18 years of age, ECOG PS of ≤2, no existing peripheral neuropathy or coronary artery disease, no prior treatment with neurotoxic chemotherapy, and no concurrent treatment with neuropathic or opioid pain medication. Planned sample size was 100 patients per arm, to provide 80% power to detect a difference in incidence of grade 2+ SN toxicity from 25% in the placebo group to 10% in the vitamin E group. Results: Two-hundred seven pts were enrolled between 12/01/2006 and 12/14/2007. Cytotoxic agents included taxanes (109), cisplatin (8), carboplatin (2), oxaliplatin (50) or combination (20). Eleven pts canceled prior to starting treatment and there were 7 ineligible pts on study. Thus there were 189 evaluable pts included in the current analysis. In this analysis, there was no difference in the incidence of grade 2+ SN between the 2 arms (vitamin E- 34% [95% CI- 25.0–44.8%] placebo- 29% [20.1–39.4%]; P=0.43). There, likewise, were no significant differences between treatment arms for time to onset of neuropathy (P= 0.72), for chemotherapy dose reductions due to neuropathy (P= 0.21) or patient questionnaire reported neuropathy symptoms. The treatment was well tolerated overall. Conclusions: Vitamin E did not appear to reduce the incidence of sensory neuropathy in the studied group of patients receiving neurotoxic chemotherapy but it appeared to be well tolerated. No significant financial relationships to disclose.

9513 Background: Hot flashes are a major problem in many women for which better treatment options are needed. Given the known efficacy of gabapentin for decreasing hot flashes, it was decided to evaluate pregabalin, with hopes that it would work better and/or with fewer toxicities. Methods: A three-arm, double-blinded, placebo-controlled randomized trial was developed. Women with bothersome hot flashes (at least 28/week) were randomized to receive either a placebo or target pregabalin oral doses of 75 mg bid or 150 mg bid (starting at 50 mg/d and then increasing the dose at weekly intervals to 50 mg bid, then 75 mg bid, and then, in the higher dose arm, 150 mg bid); patients were treated for 6 weeks. Hot flash numbers and scores (hot flash number times mean severity) were measured using a validated daily hot flash diary. A one-week baseline period preceded initiation of study tablets. The primary endpoint was the average intra-patient difference in hot flash score between baseline and week six, comparing the higher dose pregabalin arm and the placebo arm. With the planned sample size of 55 patients per arm, there was an 80% power and two-sided 5% Type I error rate to detect a difference of 0.54 standard deviations, or 1.08 hot flashes per day, or 2.7 units of hot flash score per day. Results: 207 patients were randomized between 6/20/2008 and 8/21/2008. The study arms were well balanced. Mean/median daily hot flash scores and frequencies for all pts at baseline were 15.7/13.4 and 8.3/7.7, respectively. The table shows the decreases in hot flashes from the baseline to the sixth treatment week. Larger numbers illustrate greater hot flash reductions. Toxicity information, quality of life information, and information regarding the effects of hot flashes on subjective symptoms will be available at the meeting time. Conclusions: Pregabalin reduces hot flashes in women. There appears to be similar effects with both studied doses. [Table: see text] No significant financial relationships to disclose.

1020 Background: Trastuzumab-containing regimes have dramatically improved outcome of patients with HER2+ breast cancer. Efforts to improve efficacy and tolerability of combination regimens with this monoclonal antibody are important for patient care. Thus, we conducted a multi-institutional phase II study of a triplet combination in patients eligible to receive either first- or second-line treatment for HER2+ metastatic breast cancer (MBC). Methods: A phase II study designed to test that the true confirmed response rate (CRR) was at most 45% versus a true CRR of at least 65% was done (March 2005-June 2008). This design required that at least 25/45 confirmed responses in evaluable patients for the treatment to be considered promising. Patients received capecitabine 825 mg/m2 po (days 1–14), vinorelbine intravenously (IV) 25 mg/m2 days 1 and 8 every 3 weeks and trastuzumab IV 8mg/kg day 1, week 1, and then 6 mg/kg q 3 weeks. Tissue and blood have been collected for future studies on biomarkers. Results: 47 women were accrued, one patient cancelled participation prior to receiving any study drug, and another had a major protocol violation. 45 patients were evaluable and 30 (67%) achieved a confirmed response, (26 patients, 58% had a confirmed partial response and 4 patients, 9% had a confrimed complete response). Median progression free survival was 11.3 months (95% CI 8.4–23.2 months), median overall survival was 27.2 months (95% CI: 26.6-NA months), and among the 30 responders, the median duration of response time was 15.5 months (95% 7.7–26.1 months). The most common grade 3 events include neutropenia 61%, fatigue 13%, skin reaction-hand-foot 11%, and leukopenia 11%. Alopecia was not noted with this regimen. Conclusions: This triplet combination is effective, safe, and is promising in patients with HER2+ MBC. A phase III study should be conducted to compare the best doublet with this triplet combination whether this would lead to better clinical outcomes. [Table: see text]

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1, a member of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the mammalian target of rapamycin (mTOR) could produce tumor responses in patients (pts) with MCL. Patients and Methods: Eligible pts had biopsy-proven, cyclin D1 positive MCL and had relapsed or were refractory to therapy. Pts received CCI-779 250 mg IV every week as a single agent. Pts were re-staged after 1 cycle (4 doses) and every 3 cycles thereafter. Pts with a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission (CR) and then were observed. Results: Thirty-five pts were enrolled and evaluable for toxicity; 1 patient had MCL by histology but was cyclin D1 negative and ineligible for efficacy evaluation. The median age was 70 years (range, 38–89), 91% were stage 4, and 69% had ≥ 2 extranodal sites. Pts had received a median of 3 prior therapies (range, 1–11) and 54% were refractory to their last treatment. The overall response rate was 38% (13/34) with 1 CR (3%) and 12 PRs (35%), surpassing the pre-defined criteria for a promising agent. Responses tended to occur rapidly with median time to response of 1 month (range, 1–8). To date, 26 patients have progressed, with a median time-to-progression of 6.8 months (95% CI: 3.8 – 9.7). Median duration of response for the 13 responders was 5.7 months (95% CI: 5.2 – 13.2). Overall, 32 out of 35 patients who received treatment had grade 3 or 4 toxicity. The most common toxicities were hematologic with grade 3 (n=24) or grade 4 (n=4). Thrombocytopenia was the most frequent grade 3/4 toxicity (n=25) and the largest cause of dose-reductions, although counts typically recovered within one week. Only 4 patients could tolerate sustained 250 mg per week throughout their treatment (including one who went on to alternate treatment after 1 cycle) and the median dose/month was 175 mg. Conclusions: Single-agent CCI-779 has substantial anti-tumor activity in relapsed MCL. This study demonstrates that agents, which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The high response rate warrants further studies of this agent in MCL, but the high incidence of hematologic toxicity suggests that a lower dose should be explored. CCI-779 at 25mg is currently being evaluated in MCL through an NCCTG trial

8527 Background: Minority patients (MP) suffer deficits in access to care and socioeconomic status. This study uses a patient-level pooled analysis to explore whether these deficits translate into quality of life (QOL) differences between MP and non-MP on clinical trials. Method: Baseline QOL scores were combined from 47 clinical trials (6,513 patients) conducted either at the Mayo Clinic Cancer Center or in the North Central Cancer Treatment Group. QOL scales used were the Uniscale, Linear Analogue Self Assessment (LASA), Symptom Distress Scale (SDS), Profile of Mood States (POMS) and Functional Assessment of Cancer Therapy - General (Fact-G). Fisher’s Exact tests and linear regression adjusted for age, site, and performance score. Survival data was compared using the method of Kaplan-Meier. Results: Eight percent (531) of patients self-reported as MP (0.45% American Indian/Alaskan Native, 0.7% Asian, 5% Black/African American, 1.5% Hispanic, 0.1% Native Hawaiian and 0.3% Other). MP had no meaningful deficits in overall QOL or the SDS and were slightly worse on FACT-G total score, physical, social/family, functional, and SDS nausea severity. MP among lung cancer patients reported greater nausea (58 vs 69) and sleep problems (34 vs 54), with neurological cancers reported worse emotional well-being (53 vs 74), and with GI tumors had lower social/family well-being (60 vs 67). Regression models confirmed these results. Median survival time was shorter for MP (198 vs 310 days, p=0.001) but was not significant after adjusting for disease severity. Conclusions: MP on these clinical trials did not report large QOL deficits at baseline relative to non-MP. MP did indicate small deficits in physical, social, and emotional subscales. MP experienced large tumor-specific deficits for a few QOL domains that might bear further attention. [Table: see text] No significant financial relationships to disclose.

3501 Background: Cumulative neurotoxicity commonly leads to early discontinuation of oxaliplatin-based therapy. In a relatively small, prematurely-discontinued, randomized study, IV CaMg was associated with reduced oxaliplatin-induced sNT (Grothey, JCO, 2011). N08CB was designed to definitively test whether IV CaMg significantly decreases cumulative oxaliplatin-related sNT. Methods: 353 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to 3 arms: IV CaMg (1g calcium gluconate, 1g magnesium sulfate) before and after oxaliplatin vs PL before and after vs CaMg before and PL after. The primary endpoint was cumulative sNT repeatedly measured by the sensory subscale of the EORTC QLQ-CIPN20. Secondary endpoints, using CTCAE 4.0 and an oxaliplatin specific neurotoxicity scale, were also assessed. Acute neuropathy data were also collected for 5 days following each oxaliplatin dose. The area under the curve (AUC) of the sensory subscale during the treatment cycles was used as summary measures for comparison. The Wilcoxon rank-sum tests were conducted for each treatment versus placebo arm, at 2.5%, adjusting for multiplicity using Bonferroni’s approach. Results: CaMg did not reduce cumulative sNT. Primary and secondary analyses data are summarized in the Table. In addition, there were no significant differences between arms regarding oxaliplatin administered doses or chemotherapy discontinuation rates. Also, there were no substantial differences in acute neuropathy scores or side-effects between study arms. Conclusions: This study does not demonstrate any activity of IV CaMg as a neuroprotectant against oxaliplatin-induced neurotoxicity. Clinical trial information: NCT01099449. [Table: see text]

7605 Background: Overall survival (OS) can be partitioned into progression-free survival (PFS) and PPS. PPS helps to understand trial results, especially when PFS and OS data on trial treatment effects are discordant. At ASCO 2011, we reported that the magnitude of difference in the PFS estimates using different DP date methods was large enough to alter trial conclusions. Here, we investigate the impact of the DP date method on 1) PPS estimates, and 2) predictive utility of DP metrics on subsequent OS (SOS). Methods: Individual patient (pt) data from 14 trials were pooled. DP date was determined using: reported progression date (RPD) (method 1, M1), one day after last progression-free (PF) scan (M2), and midpoint between last PF scan and RPD (M3). PPS was estimated using the method of Kaplan-Meier for the 3 DP date methods. A flexible landmark analysis at 2, 4, and 6 months (mos) using Cox proportional hazards model was used to assess the impact of DP status (progression versus no-progression) on SOS (using M1, M2, or M3). Results: Among NSCLC (SCLC), 87% (91%) of pts reported DP. As expected, the PPS estimates were the lowest for RPD, highest for M2, and in-between for M3 (a direct consequence of the DP date method); with no difference by arm for the randomized trials. Regardless of the DP date method, patients who were progression-free had improved SOS (NSCLC: Hazard ratio, HR<=0.33; p < 0.0001; SCLC: HR<=0.48; p < 0.002) at each landmark time point, with comparable concordance index (SCLC: 0.57-0.65; NSCLC: 0.63-0.67), i.e., ability to discriminate patients with different SOS outcomes. Conclusions: While the DP date methods do not impact the predictive utility of the DP metrics, they significantly impact PPS estimates. The translation of a significant treatment effect on PFS to an effect on OS is influenced by PPS (longer PPS dilutes effect on OS). Standards for declaring DP date are thus critical to trial design and for trial go/no-go decisions. [Table: see text]