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PDF file, 1001K, Methods; Supplementary Table 1 - Temporary dose interruptions due to adverse events; Supplementary Table 2 - Changes in biomarker levels between baseline and Day 15; Supplementary Figure 1: Schematic showing dosing cohorts, DLTs and the MTD; Supplementary Figure 2 - Case-study: FDG-PET uptake at baseline.

Purpose: This phase I study of the mitogen-activated protein/extracellular signal–regulated kinase inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors.Patients and Methods: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-week cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule.Results: Forty-nine patients were enrolled. DLTs were blurred vision (n = 1) and elevated creatine phosphokinase (n = 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approximately 4 hours. At the MTD, target inhibition, assessed by suppression of extracellular signal–regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC50). Of the patients evaluable for response, clinical benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a reduction in fluorodeoxyglucose uptake by positron emission tomography between baseline and day 15.Conclusion: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors. Clin Cancer Res; 18(17); 4794–805. ©2012 AACR.

Background: Cytotoxic chemotherapy (CT) in combination with trastuzumab and pertuzumab (HP) is standard of care for patients (pts) diagnosed with HER2-positive early breast cancer (EBC). While highly effective, the toxicity associated with CT is challenging. In KRISTINE/TRIO-021, neoadjuvant T-DM1 was combined with pertuzumab (KP) and compared to standard TCHP. Pts. received six cycles of neoadjuvant treatment followed by adjuvant therapy (KP or HP). Pts. in the KP arm were allowed to receive standard adjuvant CT. Pathologic complete response (pCR) rate was significantly lower with KP versus TCHP and more pts. had disease progression prior to surgery with KP, resulting in a meaningfully lower event-free survival rate vs. the control (85.3% vs 94.2%). However, 3-year invasive disease-free survival was numerically similar in both arms. Neoadjuvant KP demonstrated less toxicity than standard CT, although treatment discontinuation was higher post-surgery. Association of KP and TCHP with treatment-related amenorrhea (TRA) in premenopausal EBC pts. has not been ascertained. Methods: All pts. with premenopausal status at study entry (those not meeting the menopause definition based on National Comprehensive Cancer Network Guidelines v3, 2012) and with menstrual period documented within 3 months of randomization, were independently evaluated for presence or absence of TRA by two reviewers. TRA, a prespecified exploratory endpoint of KRISTINE, was defined as cessation of menstruation for >12 months in the absence of treatment with ovarian suppression or other interventions that can induce amenorrhea. Pts. were followed from the time of study entry through the 3-year follow up period after surgery. For cases with inconsistent determination between the two reviewers, a third reviewer adjudicated. TRA rates were calculated per arm, hormone-receptor (HR) status, adjuvant CT and age group. Proportions were compared by estimating the odds ratio (OR) and the 95% confidence interval. Results: Of 444 pts. enrolled, 205 were excluded based on being post-menopausal per NCCN guidelines. Of 239 pts. remaining, 56 were excluded due to insufficient data. The median age of pts. included was 40 years (range: 22-53) for TCHP and 42.5 (range: 23-52) for KP. TRA was observed in 55% (50/91) of pts. treated with TCHP compared to 30% (28/92) treated with KP (OR=2.79; 95% CI 1.52-5.12). In pts. with HR-positive EBC, TRA occurred in 62% with TCHP vs 35% for KP (OR=2.998; 95% CI 1.44-6.25). In those with HR-negative EBC, TRA was observed in 42% with TCHP vs. 21% with KP (OR=2.77; 95% CI 0.88-8.72). In the KP arm, TRA was observed in 38% (8/21) of pts. treated with standard adjuvant CT vs. 28% (20/71) of those that did not (OR 1.57; 95% CI 0.57-4.36). For women age ≤ 40, the rate of TRA was 38% with TCHP vs. 17% with KP (OR=3.00; 95% CI 1.05-8.60). For those > 40 years, TRA was observed in 74% treated with TCHP vs. 39% of those with KP (OR=4.50; 95% CI 1.88-10.73). Conclusion: The rate of TRA with standard TCHP is nearly double that observed with KP, suggesting that targeted CT with an antibody-drug conjugate regimen is associated with less gonadal toxicity. Rates of TRA are higher in women over the age of 40 for each treatment arm however KP is associated with lower rate of TRA in each age group. Association of TRA with efficacy outcomes (pCR, iDFS) will be presented. Citation Format: Sara A Hurvitz, Rodrigo Fresco, Karen Afenjar, Daniil Stroyakovskiy, Chiun-Sheng Huang, Hans Wildiers, Kyung Hae Jung, Jean-François Boileau, Mario Campone, Miguel Martín, Vicente Valero, Joseph A. Sparano, W. Fraser Symmans, Peter A. Fasching, Alastair M. Thompson, Nadia Harbeck, Vanesa López-Valverde, Chunyan Song, Thomas Boulet, Eleonora Restuccia, Dennis J. Slamon. Treatment-related amenorrhea with T-DM1 plus pertuzumab (KP) is lower than with docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) in the phase III neoadjuvant KRISTINE trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD12-06.

PURPOSE The KRISTINE study compared neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, trastuzumab plus P (TCH+P) for the treatment human epidermal growth factor receptor 2–positive stage II to III breast cancer. T-DM1+P led to a lower pathologic complete response rate (44.4% v 55.7%; P = .016), but fewer grade 3 or greater and serious adverse events (AEs). Here, we present 3-year outcomes from KRISTINE. METHODS Patients were randomly assigned to neoadjuvant T-DM1+P or TCH+P every 3 weeks for six cycles. Patients who received T-DM1+P continued adjuvant T-DM1+P, and patients who received TCH+P received adjuvant trastuzumab plus pertuzumab. Secondary end points included event-free survival (EFS), overall survival, patient-reported outcomes (measured from random assignment), and invasive disease-free survival (IDFS; measured from surgery). RESULTS Of patients, 444 were randomly assigned (T-DM1+P, n = 223; TCH+P, n = 221). Median follow-up was 37 months. Risk of an EFS event was higher with TDM-1+P (hazard ratio [HR], 2.61 [95% CI, 1.36 to 4.98]) with more locoregional progression events before surgery (15 [6.7%] v 0). Risk of an IDFS event after surgery was similar between arms (HR, 1.11 [95% CI, 0.52 to 2.40]). Pathologic complete response was associated with a reduced risk of an IDFS event (HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm. Overall, grade 3 or greater AEs (31.8% v 67.7%) were less common with T-DM1+P. During adjuvant treatment, grade 3 or greater AEs (24.5% v 9.9%) and AEs leading to treatment discontinuation (18.4% v 3.8%) were more common with T-DM1+P. Patient-reported outcomes favored T-DM1+P during neoadjuvant treatment and were similar to trastuzumab plus pertuzumab during adjuvant treatment. CONCLUSION Compared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadjuvant treatment, and more AEs leading to treatment discontinuation during adjuvant treatment.

Purpose: This phase I study of the mitogen-activated protein/extracellular signal–regulated kinase inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors. Patients and Methods: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-week cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule. Results: Forty-nine patients were enrolled. DLTs were blurred vision (n = 1) and elevated creatine phosphokinase (n = 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approximately 4 hours. At the MTD, target inhibition, assessed by suppression of extracellular signal–regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC50). Of the patients evaluable for response, clinical benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a reduction in fluorodeoxyglucose uptake by positron emission tomography between baseline and day 15. Conclusion: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors. Clin Cancer Res; 18(17); 4794–805. ©2012 AACR.

669 Background: Imgatuzumab, a humanized engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, showed promising clinical activity in a phase I trial including KRAS MT mCRC. This multicenter phase II study (NCT01326000) aimed to compare the combination of imgatuzumab with FOLFIRI to cetuximab plus FOLFIRI or FOLFIRI alone as second-line treatment in patients with both KRAS e2WT or e2MT mCRC. Methods: Patients underwent a mandatory fresh tumor biopsy at screening to assess KRAS exon 2 status. KRAS e2WT patients were randomized (1:1) to treatment groups 1 or 2 to receive imgatuzumab (1,400 mg IV on day 1 and 8 then q2-weekly) or cetuximab (400 mg/m2 IV on day 1 followed by 250 mg/m2 IV q-weekly) respectively plus FOLFIRI (standard IV chemotherapy). KRAS e2MT patients were randomized to groups 3 and 4 to receive imgatuzumab plus FOLFIRI or FOLFIRI alone respectively. Patients were stratified by EGFR expression, time to disease progression on first line treatment and prior treatment with bevacizumab. A run-in phase (n=6/group) was performed to confirm tolerability before recruitment proceeded. Results: 169 patients with an evaluable fresh tumor biopsy were randomized. Median PFS (Investigator reported) was 7.3 months in group 1 versus 6.1 in group 2 (HR, 1.13; 95% CI 0.69-1.86) and 5.2 months in group 3 versus 4.3 in group 4 (HR, 0.94; 95% CI 0.57-1.54). Adverse events of ≥ grade 3 included rash (42.5%, 9.8%, 31.8%, 0% in groups 1, 2, 3 and 4 respectively), hypomagnesemia (30.0%, 4.9%, 22.7%, 0% respectively) and neutropenia (20.0%, 29.3%, 25.0%, 21.4% respectively). Conclusions: The outcome was negative with respect to the primary efficacy endpoint (PFS) with no benefit seen for the addition of imgatuzumab to FOLFIRI in second-line in both KRAS e2WT and e2MT populations. We demonstrated that collection of fresh tumor biopsy is feasible in pretreated CRC. Clinical trial information: NCT01326000.

We investigated whether renovascular hypertension alters vasodilatation mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) and the influence of the superoxide dismutase mimetic tempol on vasodilatation. One-kidney one-clip hypertensive Sprague-Dawley rats, treated with either vehicle or tempol (from weeks 5 to 10 after placement of the clip), and uninephrectomized control rats were investigated. In renal hypertensive rats systolic blood pressure increased to 171+/-6 mmHg (n=10), while in tempol-treated rats systolic blood pressure remained normal (139+/-7 mmHg, n=5). In isolated pressurized mesenteric small arteries NO-mediated dilatation was obtained by increasing flow rate and EDHF-mediated dilatation by acetylcholine. In arteries from hypertensive rats, flow-induced dilatation was blunted, as compared to normotensive and tempol-treated rats, while acetylcholine-induced dilatation remained normal. Measured by dihydroethidium staining there was an increased amount of superoxide in arteries from vehicle-treated rats, but not from tempol-treated rats. Expression by immunoblotting of endothelial NO synthase and the NAD(P)H oxidase subunit p47phox remained unaffected by high blood pressure and tempol treatment. Simultaneous measurements of NO-concentration and relaxation were performed in isolated coronary arteries from the same animals. As compared to vehicle-treated rats, both acetylcholine-induced relaxation and NO-concentration increased in arteries from tempol-treated animals, while only the relaxation was improved by the NO donor, S-nitroso-N-acetylpenicillamine (SNAP). In conclusion renovascular hypertension selectively inhibits flow-induced NO-mediated vasodilatation, while EDHF-type vasodilatation remains unaffected, suggesting that high blood pressure leads to increased generation of superoxide contributing to decreased NO bioavailability. Furthermore, the abnormal endothelium function can be corrected by tempol treatment, but this seems to involve mechanisms partly independent of NO.