S. N. Holden

Phase I Study of Trastuzumab-DM1, an HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer

PURPOSE Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that uses trastuzumab to specifically deliver the maytansinoid antimicrotubule agent DM1 to HER2-positive cells. This first-in-human study of T-DM1 evaluated safety, pharmacokinetics, and preliminary activity of T-DM1 in patients with advanced HER2-positive breast cancer. PATIENTS AND METHODS Successive cohorts of patients who had progressed on trastuzumab-based therapy received escalating doses of T-DM1. Outcomes were assessed by standard solid-tumor phase I methods. RESULTS Twenty-four patients who had received a median of four prior chemotherapeutic agents for metastatic disease received T-DM1 at 0.3 mg/kg to 4.8 mg/kg on an every-3-weeks schedule. Transient thrombocytopenia was dose-limiting at 4.8 mg/kg; the maximum-tolerated dose (MTD) was 3.6 mg/kg. The half-life of T-DM1 at the MTD was 3.5 days, with peak DM1 levels < 10 ng/mL. Clearance at doses < 1.2 mg/kg was faster than at higher doses. Common drug-related adverse events (AEs) included grade < or = 2 thrombocytopenia, elevated transaminases, fatigue, nausea, and anemia. No grade > 1 nausea, vomiting, alopecia, or neuropathy events and no cardiac effects requiring dose modification were reported. The clinical benefit rate (objective response plus stable disease at 6 months) among 15 patients treated at the MTD was 73%, including five objective responses. The confirmed response rate in patients with measurable disease at the MTD (n = 9) was 44%. CONCLUSION At the MTD of 3.6 mg/kg every 3 weeks, T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-positive breast cancer are under way.

Impact of Vascular Endothelial Growth Factor-A Expression, Thrombospondin-2 Expression, and Microvessel Density on the Treatment Effect of Bevacizumab in Metastatic Colorectal Cancer

PURPOSE Bevacizumab is a monoclonal antibody to vascular endothelial growth factor-A (VEGF). In the pivotal trial in metastatic colorectal cancer (mCRC), addition of bevacizumab to first-line irinotecan, fluorouracil, and leucovorin (IFL) significantly prolonged median survival. The aim of these retrospective subset analyses was to evaluate VEGF, thrombospondin-2 (THBS-2), and microvessel density (MVD) as prognostic factors and/or predictors of benefit from bevacizumab. PATIENTS AND METHODS In the pivotal trial, 813 patients with untreated mCRC were randomly assigned to receive IFL plus bevacizumab or placebo. Of 312 tissue samples collected (285 primaries, 27 metastases), outcome data were available for 278 (153 bevacizumab, 125 placebo). Epithelial and stromal VEGF expression were assessed by in situ hybridization (ISH) and immunohistochemistry on tissue microarrays and whole sections. Stromal THBS-2 expression was examined by ISH on tissue microarrays. MVD was quantified by Chalkley count. Overall survival was associated with these variables in retrospective subset analyses. RESULTS In all subgroups, estimated hazard ratios (HRs) for risk of death were < 1 for bevacizumab-treated patients regardless of the level of VEGF or THBS-2 expression or MVD. Patients with a high THBS-2 score showed a nonsignificant improvement in survival following bevacizumab treatment (HR = 0.11; 95% CI, 0.02 to 0.51) compared to patients with a low score (HR = 0.65; 95% CI, 0.41 to 1.02); interaction analysis P = .22. VEGF or THBS-2 expression and MVD were not significant prognostic factors. CONCLUSION These exploratory analyses suggest that in patients with mCRC addition of bevacizumab to IFL improves survival regardless of the level of VEGF or THBS-2 expression, or MVD.

Predicting benefit from anti-angiogenic agents in malignancy

A high probability of benefit is desirable to justify the choice of anti-angiogenic therapy from an ever-expanding list of expensive new anticancer agents. However, biomarkers of response to cytotoxic agents are not optimal for predicting benefit from anti-angiogenic drugs. This discussion will focus on both preclinical and clinical research to identify biomarkers for anti-angiogenic therapies that can inform dosing, early clinical benefit, initial drug choice, emerging resistance and second-line treatments.

Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy?

A majority of the novel orally administered, molecularly targeted anticancer therapies are weak bases that exhibit pH‐dependent solubility, and suppression of gastric acidity with acid‐reducing agents could impair their absorption. In addition, a majority of cancer patients frequently take acid‐reducing agents to alleviate symptoms of gastroesophageal reflux disease, thereby raising the potential for a common but underappreciated drug–drug interaction (DDI) that could decrease the exposure of anticancer medication and result in subsequent failure of therapy. This article is a review of the available clinical literature describing the extent of the interaction between 15 orally administered, small‐molecule targeted anticancer therapies and acid‐reducing agents. The currently available clinical data suggest that the magnitude of this DDI is largest for compounds whose in vitro solubility varies over the pH range 1–4. This range represents the normal physiological gastric acidity (pH ~1) and gastric acidity while on an acid‐reducing agent (pH ~4).

A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2–positive breast cancer†‡

We conducted a phase 1, multicenter, open‐label, dose‐escalation study (TDM3569g) to assess the safety, tolerability, and pharmacokinetics of single‐agent trastuzumab emtansine (T‐DM1) administered weekly and once every 3 weeks in patients with HER2‐positive metastatic breast cancer previously treated with trastuzumab. The weekly dose results are described here.

Trastuzumab Emtansine (T-DM1): A Novel Agent for Targeting HER2 Breast Cancer

Increased understanding of the molecular mechanisms of tumorigenesis has led to the development of novel agents that target tumor cells with minimal effects on normal cells. The success of this approach is exemplified by the development of monoclonal antibodies directed toward antigens expressed selectively by tumor cells. The conjugation of these monoclonal antibodies with potent cytotoxic drugs has the potential to further improve efficacy while retaining a favorable safety profile. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) currently in clinical development. It combines the humanized antibody trastuzumab, which targets the human epidermal growth factor receptor 2 (HER2) receptor on cancer cells, and the potent antimicrotubule agent DM1 using a unique highly stable linker. When T-DM1 binds to HER2, a proportion of the receptors are thought to be internalized by the process of receptor endocytosis, followed by the intracellular release of an active form of DM1, which in turn kills the tumor cell. This review presents the rationale for the development of T-DM1 and summarizes the preclinical and clinical data for this novel agent for the treatment of breast cancer.

A phase I study of weekly dosing of trastuzumab-DM1 (T-DM1) in patients with advanced HER2+ breast cancer.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #3136 Background: T-DM1, a novel HER2 antibody-drug conjugate (ADC) in development for HER2+ breast cancer (BC), combines activity of trastuzumab (T) with the targeted delivery of maytansinoid DM1 (potent antimicrotubule agent) to HER2-expressing cells. DM1 binds tubulin competitively with vinca alkaloids, 20-100x more potently than vincristine. It is bound to T by MCC, a linker that is stable with protease activity and under many pH or redox conditions. T-DM1 is the first ADC with an MCC linker to enter clinical trials. Main preclinical AEs were reversible transaminase (TA) elevations, reversible platelet decreases, and neuropathy. A phase I study of T-DM1 every 3 wks (q3w) in patients (pts) with advanced HER2+ BC who progressed on T-containing chemotherapy regimen, the maximum tolerated dose (MTD) was 3.6 mg/kg, with DLT of grade (Gr) 4 thrombocytopenia (TCP); tumor responses were seen in 5 of 9 pts (4 confirmed, 44%) with measurable disease treated at MTD. We undertook this dose escalation study of T-DM1 given once/wk (q1w) to explore pharmacokinetics (PK), safety, and tolerability of more frequent dosing. Methods: Pts with advanced HER2+ BC who had progressed on a T-containing chemotherapy regimen received T-DM1 IV q1w continuously. Dose levels were escalated in successive 3+3 cohorts if DLT was seen in <1/3 of pts within 21 days of Cycle 1 Day 1. Results: As of 19 May 2008, enrollment is complete with 27 pts (15 at the MTD). Data is available for 19 pts [median age 54.0 (range 41-71); all PS 0-1; median number prior metastatic chemo agents 5.0 (range 2-8); median wks of prior trastuzumab 122 (range 29-325)] who have received 246 doses of T-DM1 at 1.2, 1.6, 2.0, 2.4, and 2.9 mg/kg. Common related AEs include fatigue (Gr1, 3 pts; Gr2, 4 pts; Gr3, 1 pt), thrombocytopenia (Gr 1, 4 pts; Gr2, 3 pts; Gr3, 2 pts), nausea (Gr1, 7 pts; Gr 2, 1 pt), TA elevations (Gr1, 1 pt; Gr2, 4 pts; Gr3, 1 pt), vomiting (Gr1, 3 pts; Gr2, 1 pt) and headache (Gr1, 2 pts; Gr2, 1 pt). Dose-limiting toxicity was seen in 2 pts at 2.9 mg/kg (toxicity preventing retreatment on Cycle 1 Day 8, from Gr2-3 thrombocytopenia). No Gr4 AEs or cardiac toxicity were seen. Preliminary PK analyses suggest that steady-state T-DM1 exposure at 2.4 mg/kg q1w will be ∼2x that associated with 3.6 mg/kg q3w. Of 15 pts evaluable for response, 9 had partial responses (8 confirmed, 53%). Conclusions: The MTD of T-DM1 on a weekly schedule is 2.4 mg/kg. Related Gr ≥2 AEs were reversible and manageable. The activity and safety results observed on q1w dosing were consistent with q3w dosing, supporting further study. Three Phase II trials of q3w T-DM1 in advanced HER2+ BC will enroll pts in 2008; preliminary results from the first trial will be reported in 2008. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3136.

Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors

PurposeThe purpose of this study was to evaluate the effect of bevacizumab on the pharmacokinetics (PK) of irinotecan and its active metabolite. Exploratory analyses of the impact of variability in uridine diphosphate glucuronosyltransferase 1A (UGT1A) genes on irinotecan metabolism and toxicity were conducted.MethodsThis was an open-labeled, fixed-sequence study of bevacizumab with FOLFIRI (irinotecan, leucovorin, and infusional 5-fluorouracil). Pharmacokinetic assessments were conducted in cycles 1 and 3.ResultsForty-five subjects were enrolled. No difference in dose-normalized AUC0–last for irinotecan and SN-38 between irinotecan administered alone or in combination with bevacizumab was identified. Leukopenia was associated with higher exposure to both irinotecan and SN-38. UGT1A1 polymorphisms were associated with variability in irinotecan PK. Gastrointestinal toxicity was associated with UGT1A6 genotype. No other associations between UGT1A genotypes and toxicity were detected.ConclusionBevacizumab does not affect irinotecan PK when administered concurrently. A variety of pharmacogenetic relationships may influence the pharmacokinetics of irinotecan and its toxicity.

Impact of Food and the Proton Pump Inhibitor Rabeprazole on the Pharmacokinetics of GDC-0941 in Healthy Volunteers: Bench to Bedside Investigation of pH-Dependent Solubility

GDC-0941 is an orally administered potent, selective pan-inhibitor of phosphatidylinositol 3-kinases (PI3Ks) with good preclinical antitumor activity in xenograft models and favorable pharmacokinetics and tolerability in phase 1 trials, and it is currently being investigated in phase II clinical trials as an anti-cancer agent. In vitro solubility and dissolution studies suggested that GDC-0941, a weak base, displays significant pH-dependent solubility. Moreover, preclinical studies conducted in famotidine-induced hypochlorhydric dog suggested that the pharmacokinetics of GDC-0941 may be sensitive to pharmacologically induced hypochlorhydria. To investigate the clinical significance of food and pH-dependent solubility on GDC-0941 pharmacokinetics a four-period, two-sequence, open-label, randomized, crossover study was conducted in healthy volunteers. During the fasting state, GDC-0941 was rapidly absorbed with a median Tmax of 2 h. The presence of a high-fat meal delayed the absorption of GDC-0941, with a median Tmax of 4 h and a modest increase in AUC relative to the fasted state, with an estimated geometric mean ratio (GMR, 90% CI) of fed/fasted of 1.28 (1.08, 1.51) for AUC0-∞ and 0.87 (0.70, 1.06) for Cmax. The effect of rabeprazole (model PPI) coadministration on the pharmacokinetics of GDC-0941 was evaluated in the fasted and fed state. When comparing the effect of rabeprazole + GDC-0941 (fasted) to baseline GDC-0941 absorption in a fasted state, GDC-0941 median Tmax was unchanged, however, both Cmax and AUC0-∞ decreased significantly after pretreatment with rabeprazole, with an estimated GMR (90% CI) of 0.31 (0.21, 0.46) and 0.46 (0.35, 0.61), respectively for both parameters. When rabeprazole was administered in the presence of the high-fat meal, the impact of food did not fully reverse the pH effect; the overall effect of rabeprazole on AUC0-∞ was somewhat attenuated by the high-fat meal (estimate GMR of 0.57, with 90% CI, 0.50, 0.65) but unchanged for the Cmax (estimate of 0.43, with 90% CI, 0.37, 0.50). The results of the current investigations emphasize the complex nature of physicochemical interactions and the importance of gastric acid for the dissolution and solubilization processes of GDC-0941. Given these findings, dosing of GDC-0941 in clinical trials was not constrained relative to fasted/fed states, but the concomitant use of ARAs was restricted. Mitigation strategies to limit the influence of pH on exposure of molecularly targeted agents such as GDC-0941 with pH-dependent solubility are discussed.

Dulanermin with rituximab in patients with relapsed indolent B-cell lymphoma: an open-label phase 1b/2 randomised study

BACKGROUND Dulanermin-a non-polyhistidine-tagged soluble recombinant human apoptosis ligand 2 (Apo2L) or tumour-necrosis-factor-related apoptosis-inducing-ligand (TRAIL)-has pro-apoptotic activity in a range of cancers and synergistic preclinical activity with rituximab against lymphoma in vivo. We aimed to assess the safety, pharmacokinetics, and efficacy of dulanermin and rituximab in patients with relapsed indolent B-cell non-Hodgkin lymphoma. METHODS We did an open-label phase 1b/2 randomised study. Four study centres in the USA enrolled patients into phase 1b, and 27 study centres in the USA, Italy, Australia, France, Czech Republic, New Zealand, and Poland enrolled patients into phase 2. In phase 1b, patients (age ≥18 years) with indolent B-cell non-Hodgkin lymphoma with stable disease or better lasting at least 6 months after the most recent rituximab-containing regimen were included. In phase 2, patients (age ≥18 years) with follicular lymphoma grades 1-3a were included. In phase 1b, patients received 4 mg/kg or 8 mg/kg intravenous dulanermin on days 1-5 of up to four 21-day cycles and intravenous rituximab 375 mg/m(2) weekly for up to eight doses. In phase 2, patients were randomly assigned (1:1:1) centrally by an interactive voice response system to dulanermin (8 mg/kg for a maximum of four 21-day cycles), rituximab (375 mg/m(2) weekly for up to eight doses), or both in combination, stratified by baseline follicular lymphoma International Prognostic Index (0-3 vs 4-5) and geographic site (USA vs non-USA). The primary endpoints of the phase 1b study were the safety, tolerability, and pharmacokinetics of dulanermin with rituximab. The primary endpoint of phase 2 was the proportion of patients who achieved an objective response. All patients who received any dose of study drug were included in safety analyses. Efficacy analyses were per protocol. Treatment was open label; all patients and investigators were unmasked to treatment allocation. This study is registered with ClinicalTrials.gov, NCT00400764. FINDINGS Between June 6, 2006, and Feb 15, 2007, 12 patients were enrolled in phase 1b, and between April 4, 2007, and April 20, 2009, 60 patients were enrolled in phase 2, of whom 59 were included in safety analyses and 58 in efficacy analyses. No dose-limiting toxic effects were noted in phase 1b. The most common grade 1-2 adverse events in phase 1b were fatigue (nine; 75%), rash (five; 42%), and chills, decreased appetite, diarrhoea, and nausea (four each; 33%). 19 grade 3 or higher adverse effects were noted in five (42%) patients, with 14 occurring in one patient. After treatment with 8 mg/kg of dulanermin, in six patients the mean serum peak concentration was 80 μg/mL, dropping below the minimum detectable concentration (2 ng/mL) within 24 h after the dose. The mean steady state peak and trough concentrations of rituximab were 461 μg/mL (SD 97.5) and 303 μg/mL (92.8), respectively. In phase 2, eight (14%) of 59 patients experienced 12 grade 3 or higher adverse events. In phase 2, objective responses were noted in 14 of 22 (63.6%, 95% CI 41.8-81.3) patients treated with rituximab only, 16 of 25 (64.0%, 43.1-81.5) treated with dulanermin and rituximab, and one of 11 (9.1%, 0.5-39.0) treated with dulanermin only. The study was terminated early, on May 5, 2010, because of an absence of efficacy in the combination group. INTERPRETATION The addition of dulanermin to rituximab in patients with indolent B-cell non-Hodgkin lymphoma was tolerable but did not lead to increased objective responses. This combination is not being developed further in non-Hodgkin lymphoma. FUNDING Genentech and Amgen.