Expansion Cohort Of Patients Research Articles

Phase 2A Study of Copanlisib, a Novel PI3K Inhibitor, in Patients with Indolent Lymphoma

Background: Copanlisib is a novel pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with potent preclinical inhibitory activity against both PI3K-d and PI3K-α isoforms. Preliminary results from a phase II study of copanlisib in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) have been reported (Dreyling et al., ASH 2013), with an expansion cohort for patients with aggressive lymphoma still ongoing. We report here the final results of this exploratory study for patients with indolent NHL or CLL treated with copanlisib.Methods: Patients with histologically confirmed indolent NHL or CLL and relapsed or refractory to ≥2 prior lines of treatment were eligible. Copanlisib was administered at a dose of 0.8 mg/kg as a 1 hour intravenous infusion on days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as assessed per independent radiologic review according to the response criteria for lymphoma (Cheson et al., JCO 17:1244,1999) or the guidelines for diagnosis and treatment of CLL (Hallek et al., Blood 111:5446-56, 2008). Secondary endpoints included progression-free survival (PFS) and duration of response (DOR), safety and tolerability.Results: A total of 33 patients were treated in the indolent group, including: follicular NHL (FL) = 16, CLL = 13, marginal zone lymphoma (MZL) = 3, and small lymphocytic lymphoma (SLL) = 1. Median age was 68 years (range 46-89), M/F= 15/18. The median number of previous lines of treatment was 4. Thirty patients (91%) were previously exposed to rituximab. The median number of cycles received was 5.7 (mean 7.2); the median dose and median cumulative dosage of copanlisib administered were 52 mg (87% of planned dose) and 687 mg, respectively. Five patients were dose reduced to 0.6 mg/kg and 1 to 0.4 mg/kg. The ORR as determined by independent radiologic review in 32 evaluable patients was 47%, with 1 CR, 1 uCR, and 13 PRs. By histology, there were 1 CR, 1 uCR and 5 PRs for patients with FL (ORR 47%), and 2/3 PRs for patients with MZL and 1/1 PR for the patient with SLL, for an overall ORR for patients with indolent NHL (excluding CLL) of 53%. The ORR for patients with CLL was 38% (all PRs). Overall, the median DOR was 287 days (95% CI: 56; not yet reached); median PFS was 240 days (95% CI: 173; 419). The most common adverse events (AEs) of all grades were hyperglycemia (70%), hypertension (70%), fatigue (64%), diarrhea (36%), neutropenia (36%) and anemia (33%). Grade 3-4 AEs occurring in >10% of patients included: hypertension (49% grade 3), neutropenia (30%), hyperglycemia (30% grade 3), and anemia (15%). Dose reductions, interruptions, or permanent discontinuations due to AEs were reported in 4 (12%), 21 64%), and 11 (33%) patients, respectively. There was one drug-related grade-5 event; meningitis in a heavily-pretreated CLL patient with longstanding disease-related immunodeficiency, occurring shortly after first administration of copanlisib.Conclusions: Copanlisib is active as a single-agent in heavily pretreated, advanced refractory/relapsed FL, MZL, SLL, and CLL. Copanlisib exhibited an acceptable toxicity profile, consistent with previous reports. Based on the results of this exploratory study, a phase 2B study of copanlisib in relapsed or refractory indolent NHL (after prior treatment with an alkylating agent and rituximab) has been initiated and is ongoing. DisclosuresDreyling:Bayer HealthCare: Scientific advisory board/consultant Other. Cunningham:Roche: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Merck Serono: Research Funding; Novartis: Research Funding; Astra Zeneca: Research Funding. Giurescu:Bayer Pharma AG: Employment. Mappa:Bayer S.p.A.: Employment. Grunert:Bayer Pharma AG: Employment. Childs:Bayer HealthCare Pharmaceuticals: Employment.

Efficacy, safety, pharmacokinetics and pharmacodynamics of SAR245409 (voxtalisib, XL765), an orally administered phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor: a phase 1 expansion cohort in patients with relapsed or refractory lymphoma

The maximum tolerated dose of SAR245409 (voxtalisib), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, was determined in a phase 1 dose-escalation study in advanced solid tumors. We report safety, pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of SAR245409 capsules 50 mg twice daily in an expansion cohort of 16 patients with relapsed/refractory lymphoma. The most common treatment-related adverse events (AEs) were nausea (31.3%) and diarrhea (25.0%). The most common grade 3/4 treatment-related AE was increased alanine aminotransferase (12.5%). PK results were consistent with solid tumors, confirming a relatively short steady-state half-life (mean 4.61 h). Among 12 evaluable patients, one complete response and two partial responses were achieved in patients with and without PI3K/mTOR pathway alterations. In a patient with mantle cell lymphoma achieving PR, SAR245409 was associated with significant inhibition of PI3K/mTOR and extracellular signal-related kinase (ERK) pathways. Preliminary efficacy warrants further evaluation of SAR245409 in lymphoma.

Abstract CT337: Phase I/Ib study of the PARP inhibitor (PARPi) olaparib (O) with carboplatin (C) in triple negative breast cancer (TNBC) at low genetic risk (NCT00647062)

Abstract Background: PARPi O demonstrates single agent activity in breast and ovarian cancer (Br/OvCa) pts with germline BRCA1/2 mutation (gBRCAm), and with BRCA-like phenotype. Subsets of TNBC are known to respond to therapies targeting DNA repair mechanisms. We hypothesize that O and C combination can be safely tolerated in TNBC pts and may result in benefit. Methods: Pts with recurrent or unresectable TNBC, BRCAPro score <10% or absent gBRCAm, and normal end-organ function were eligible. An open-label 3x3 dose escalation included daily oral O capsule formulation (200mg then 400 mg q12h, d1-7) with C/AUC3-5 on d2 q21d (dose level [DL]1-3). No more than 8 O/C cycles were given, followed by daily O until progression. Pts were evaluated for toxicity every 3 weeks by CTCAEv3.0, and every two cycles for response using RECISTv1.0. Results: 25 women (median age 52 [39-76]) were treated. All pts except one received prior therapy (median 5 [0-12]; prior platinum in 3pts). DLT was thrombocytopenia (DL 2: O 400mg/C AUC4 [1/6pts] and DL3: O 400mg/C AUC 5 [2/3pts]). MTD was reached at DL3 (C/AUC 5 with O 400mg capsule q12h d1-7 q21d). The expansion dose was O 400mg q12h d1-7, C/AUC 4. Gr 3/4 AEs included neutropenia (36%), thrombocytopenia (12%), and anemia (12%). 2 pts required C dose reduction and early discontinuation due to delayed marrow recovery. 13 pts (52%) needed peg-filgrastim, 6 (24%) blood transfusion, and 3 (12%) erythropoietin on at least one cycle. Responses (N=22 evaluable) included 1 CR (46+ mo), 2 PR (3, 5 mo), and 8 with SD ≥4 mo (36%; median 5 [4-7]), for a disease control rate of 50%. The pt who achieved CR had a strong family history of Br/OvCa. Peripheral blood mononuclear cells preC1, d3 or d7, and prior to C2 were collected for PAR incorporation ELISA. Paired tumor biopsies (pre/post-cycle1) were obtained from expansion cohort patients for biomarker proteomics and apoptosis endpoints; results will be presented. Conclusions: RP2D O capsule formulation 400 mg q12h d1-7 with C AUC4 q21d is tolerable in heavily pretreated TNBC pts. Interactive marrow suppression was observed. Citation Format: Victoria L. Chiou, Elise C. Kohn, Christina M. Annunziata, Lori Minasian, JoAnne Zujewski, Minshu Yu, Jay Ji, James Doroshow, Nicolas Gordon, Nicole Houston, Jung-Min Lee. Phase I/Ib study of the PARP inhibitor (PARPi) olaparib (O) with carboplatin (C) in triple negative breast cancer (TNBC) at low genetic risk (NCT00647062). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT337. doi:10.1158/1538-7445.AM2014-CT337

Abstract OT3-2-07: Phase I study of ARN-810, a novel selective estrogen receptor degrader, in post-menopausal women with locally advanced or metastatic estrogen receptor positive breast cancer

Abstract Background: Modulation of estrogen synthesis or its receptor activity represents the treatment of choice for postmenopausal women with estrogen receptor-positive (ER+) breast cancer (BC). However, despite initial response to hormonal manipulation, most tumors ultimately develop endocrine resistance. The emerging evidence that ERα can signal in both ligand-dependent and independent manner supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both modes of signaling. ARN-810 is a novel, non-steroidal ERα antagonist that induces proteasomal-mediated degradation of ERα in breast cancer cell lines at picomolar concentrations. This unique biological profile coupled with good oral pharmacokinetics (PK) produced tumor regression in both tamoxifen-sensitive and resistant BC models. Importantly, in the tamoxifen-resistant model, response to ER modulators like fulvestrant and tamoxifen was limited to tumor growth arrest. Trial Design: This is a safety and PK study of ARN-810 administered orally on a continuous daily dosing regimen with a PK lead-in. The incidence of dose limiting toxicity (DLT) will be assessed in the first cycle of treatment (28 days). Patients will be assigned to escalating doses of ARN-810 in cohorts of 3-6 patients per dose until determination of the maximum tolerated dose (MTD) and/or recommended Phase 2 Dose (RP2D) using standard 3+3 criteria. The MTD and/or RP2D will be defined as the dose with ≤1 out of 6 patients with DLT. Key eligibility criteria include postmenopausal women with locally advanced or metastatic ER+ (HER2-) BC, ECOG PS 0/1, and adequate organ function. Untreated or symptomatic brain metastases and endometrial disorders are exclusionary. At the MTD and/or RP2D, expansion cohorts of patients with disease progression after ≤2 prior hormonal therapies (≤1 in the metastatic setting) or prior therapy with fulvestrant will be enrolled. Plasma PK after first dose and at steady-state will be analyzed using non-compartmental methods. Pre- and post-treatment functional imaging with [18F]-fluoroestradiol (FES)-PET to assess tumor ER binding and paired tumor biopsies to assess for ER target modulation by IHC and gene expression will be performed. Objectives: The primary objective is to determine the MTD and/or RP2D of ARN-810. In addition to safety and PK, evaluation of biomarkers of pharmacodynamic (PD) response with FES-PET and ER target gene expression will be explored along with preliminary antitumor activity. Statistical Methods: Descriptive statistics will be used to summarize patient characteristics, treatment administration/compliance, safety and PK parameters, antitumor activity endpoints, and exploratory biomarkers. Status: To date, 3 patients have been enrolled in the first cohort at 100 mg/day. The target accrual for the dose escalation will depend upon the observed safety and PK/PD profile, which will determine the number of escalations. During dose expansion, 30 patients will be enrolled. More information about this study can be found at http://clinicaltrials.gov/ct2/show/NCT01823835?term = ARN-810. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-07.

A first-in-human phase I study of the oral Notch inhibitor LY900009 in patients with advanced cancer.

3008 Background: Notch signaling plays a critical role during stem cell self-renewal and is deregulated in multiple human cancers. The Notch pathway may be activated inappropriately by receptor mutation and overexpression as well as aberrant signals from the tumor microenvironment. LY900009 is a selective small-molecule inhibitor of gamma secretase, the enzyme that cleaves and thereby activates Notch receptors. Methods: Dose escalation was performed in cohorts of 3 patients (pts) using a modified continual reassessment method. LY900009 was taken orally thrice weekly (every MWF) during a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and clinical endpoints were evaluated. Results: 22 patients received LY900009 across 6 dose levels: 2mg (3pts), 4mg (4pts), 8mg (3pts), 15mg (3pts), 30mg (6pts), and 60mg (3pts). The most common treatment emergent adverse events possibly related to LY900009 across all grades included diarrhea (27%), vomiting (23%), nausea (18%), fatigue (23%), anorexia (23%), hypophosphatemia (14%), and rash (18%). Dose-limiting toxicities of fatigue/N/V (G3) and diarrhea (G3) were seen in 2 patients, respectively, treated at 60mg. The maximum tolerated dose (MTD) was tentatively identified at 30mg. After a single dose, mean Cmax increased from 4 to 158 ng/ml and mean AUC0-t(last) increased from 14 to 1160 ng-hr/ml. Both Cmax and AUC0-t(last) increased in a dose-dependent manner. Elimination half-life of LY900009 was approximately 2-3 hrs. LY900009 inhibited plasma levels of amyloid-β peptide (a downstream product of gamma secretase) in a dose-dependent manner with 80-90% inhibition observed in the 30 and 60mg cohorts. In the 15mg cohort, one patient had colonic biopsy that showed markedly increased glandular mucin consistent with pharmacologic inhibition of the Notch pathway. Two patients (10%) with leiomyosarcoma and ovarian cancer received 4 cycles of therapy. Conclusions: LY900009 demonstrates acceptable safety and pharmacokinetics in patients with advanced cancer. Pharmacodynamic endpoints show pathway inhibition at tolerable doses. One more cohort at 45mg is ongoing to refine the MTD and will be followed by an expansion cohort for patients with ovarian cancer.

Phase I Study of Rigosertib, an Inhibitor of the Phosphatidylinositol 3-Kinase and Polo-like Kinase 1 Pathways, Combined with Gemcitabine in Patients with Solid Tumors and Pancreatic Cancer

Rigosertib, a dual non-ATP inhibitor of polo-like kinase 1 (Plk1) and phosphoinositide 3-kinase pathways (PI3K), and gemcitabine have synergistic antitumor activity when combined in preclinical studies. This phase I study aimed to determine the recommended phase II dose (RPTD) of the combination of rigosertib and gemcitabine in patients with cancer. Patients with solid tumors who failed standard therapy or were candidates for gemcitabine-based therapy were eligible. Gemcitabine was administered on days 1, 8, and 15 on a 28-day cycle and rigosertib on days 1, 4, 8, 11, 15, and 18. Pharmacokinetic studies were conducted during an expansion cohort of patients with advanced pancreatic ductal adenocarcinoma (PDA). Forty patients were treated, 19 in the dose-escalation phase and 21 in the expansion cohort. Dose levels evaluated were (gemcitabine/rigosertib mg/m(2)): 750/600 (n = 4), 750/1,200 (n = 3), 1,000/600 (n = 3), 1,000/1,200 (n = 3), and 1,000/1,800 (n = 6 + 21). One dose-limiting toxicity (death) occurred at the highest dose level (1,000/1,800) tested. Non-dose-limiting ≥grade II/III toxicities included neutropenia, lymphopenia, thrombocytopenia, fatigue, and nausea. Grade III/IV neutropenia, thrombocytopenia, and fatigue were seen in two, one, and two patients in the expansion cohort. Partial responses were observed in PDA, thymic cancer, and Hodgkin lymphoma, including gemcitabine-pretreated PDA. The pharmacokinetic profile of rigosertib was not affected by gemcitabine. The RPTD established in this study is rigosertib 1,800 mg/m(2) and gemcitabine 1,000 mg/m(2). This regimen is well tolerated with a toxicity profile of the combination similar to the profile of gemcitabine alone. Antitumor efficacy was observed in patients who previously progressed on gemcitabine-based therapy.

Phase I clinical experience of a targeted TCR-IL2 fusion protein in patients with metastatic malignancies

3040 Background: ALT-801 is recombinant human interleukin-2 (IL-2) genetically fused to a single-chain T-cell receptor specific to a peptide antigen of human p53 presented in the context of HLA-A2 positivity. In tumor xenografts in animal models, this fusion protein demonstrated potent and targeted antitumor activity. Methods: A phase I/IIa multicenter clinical study was initiated to assess safety and clinical response of ALT-801 in patients with various metastatic malignancies. Patients screened positively for HLA-A2 and tumors expressed p53 peptide/HLA-A2 complex. In this dose escalation trial, patients received ALT-801 as a daily intravenous infusion for 4 days followed by a 10-day rest period and 4 additional daily doses. Results: Data from three dosing cohorts (0.015, 0.04, and 0.08 mg/kg/dose) indicate that ALT-801 is well-tolerated up to 0.04 mg/kg/dose. The half-life of ALT-801 is 2.5–4 hours per pharmacokinetic analysis, depending on the dose. Even at the 0.015 mg/kg level, there were sufficient concentrations of ALT-801 in the patients’ serum to fully activate cell lytic activity in vitro. Treatment with ALT-801 also led to immune activation in patients as demonstrated by elevated serum IFN-γ levels as well as an increase in IFN-γ-producing immune cells in patients’ blood. Interestingly, serum TNF-α, a major inducer of hypotension in patients receiving high-dose IL-2 treatment, was not induced in patients receiving ALT-801. Evidence of antitumor activity (i.e., stable disease, tumor shrinkage) was observed in some patients after one or two courses of ALT-801. Conclusions: At a dose of 0.04 mg/kg, ALT-801 is a well-tolerated agent that generated a vigorous immune response and demonstrated clinical efficacy in a group of patients with various metastatic malignancies. An expansion cohort of patients is in progress at 0.04 mg/kg. [Table: see text]

Inhibition of Tumor Endothelial ERK Activation, Angiogenesis, and Tumor Growth by Sorafenib (BAY43-9006)

Activation of the Raf-MEK-ERK signal transduction pathway in endothelial cells is required for angiogenesis. Raf is the kinase most efficiently inhibited by the multikinase inhibitor sorafenib, which has shown activity against certain human cancers in clinical trials. To understand the mechanisms underlying this activity, we studied how it controlled growth of K1735 murine melanomas. Therapy caused massive regional tumor cell death accompanied by severe tumor hypoxia, decreased microvessel density, increased percentage of pericyte-covered vessels, and increased caliber and decreased arborization of vessels. These signs of K1735 angiogenesis inhibition, along with its ability to inhibit Matrigel neovascularization, showed that sorafenib is an effective anti-angiogenic agent. Extracellular signal-regulated kinase (ERK) activation in tumor endothelial cells, revealed by immunostaining for phospho-ERK and CD34, was inhibited, whereas AKT activation, revealed by phospho-AKT immunostaining, was not inhibited in K1735 and two other tumor types treated with sorafenib. Treatment decreased endothelial but not tumor cell proliferation and increased both endothelial cell and tumor cell apoptosis. These data indicate that sorafenib's anti-tumor efficacy may be primarily attributable to angiogenesis inhibition resulting from its inhibition of Raf-MEK-ERK signaling in endothelial cells. Assessing endothelial cell ERK activation in tumor bio-psies may provide mechanistic insights into and allow monitoring of sorafenib's activity in patients in clinical trials.

Phase I/II trial of BAY 43-9006, carboplatin (C) and paclitaxel (P) demonstrates preliminary antitumor activity in the expansion cohort of patients with metastatic melanoma

7507 Background: BAY 43-9006 (BAY) is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-β. BAY inhibits CRAF and BRAF (wild type/V599E mutant) and inhibits growth of melanoma xenografts. This phase I/II study was initiated to define safety, pharmacokinetics (PK), and efficacy of oral BAY administered in combination with C and P. Methods: BAY was given from day 2 to 19 of a 21 day cycle at 3 dose levels (DL): DL 1, 100 mg bid; DL 2, 200 mg bid; and DL 3, 400 mg bid. C (AUC 6) and P (225 mg/m2) were each administered on day 1. PK data were collected on days 1, 2, 22, and 23. Tumor samples were obtained pretreatment for BRAF mutation analysis. Based on responses during the dose escalation phase, melanoma pts were accrued in the expansion phase. Results: 35 melanoma patients (pts) (median age 47, PS 0–1) have been treated for at least 6 weeks and 32 are evaluable for response. Twenty-one (60%) pts received ≥ 1 prior therapy, and 68% had AJCC M1c disease. Early data shows this combination is well tolerated with no unexpected adverse events. Responses using RECIST criteria demonstrated 11 partial responses; 10 are ongoing at 3–16 months (response rate 31%). Median time to response is 3 months. Nineteen pts have stable disease as best response, and 12 remain on study for ≥3 months since entry. Median time to progression has not been reached at a median follow-up of 5 months. Preliminary PK shows lack of interaction between BAY, P, and C. There was no change in the preliminary PK values of P, the 6-OH metabolite, total platinum, or free platinum from Cycle 1 to Cycle 2. Conclusions: The combination of BAY with C and P has demonstrated activity in melanoma with a favorable safety profile and no apparent PK interaction. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Health Care; Bayer Pharmaceuticals Bayer AG; Bayer Pharmaceuticals

Phase I/II trial of BAY 43-9006, carboplatin (C) and paclitaxel (P) demonstrates preliminary antitumor activity in the expansion cohort of patients with metastatic melanoma

7507 Background: BAY 43-9006 (BAY) is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-β. BAY inhibits CRAF and BRAF (wild type/V599E mutant) and inhibits growth of melanoma xenografts. This phase I/II study was initiated to define safety, pharmacokinetics (PK), and efficacy of oral BAY administered in combination with C and P. Methods: BAY was given from day 2 to 19 of a 21 day cycle at 3 dose levels (DL): DL 1, 100 mg bid; DL 2, 200 mg bid; and DL 3, 400 mg bid. C (AUC 6) and P (225 mg/m2) were each administered on day 1. PK data were collected on days 1, 2, 22, and 23. Tumor samples were obtained pretreatment for BRAF mutation analysis. Based on responses during the dose escalation phase, melanoma pts were accrued in the expansion phase. Results: 35 melanoma patients (pts) (median age 47, PS 0–1) have been treated for at least 6 weeks an...