Evaluation of indibulin, a novel tubulin targeting-agent, in combination with capecitabine, with mathematically optimized dose scheduling

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2538-2538
Author(s):  
J. J. Lewis ◽  
M. D. Galsky ◽  
L. H. Camacho ◽  
D. M. Loesch ◽  
P. B. Komarnitsky ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Acquired Resistance ◽  
Optimal Schedule ◽  
Xenograft Model ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Drug Induced ◽  
Dose Levels

2538 Background: Indibulin (IDB) is a novel, orally available tubulin-targeting molecule that perturbs cancer cell migration and mitosis. It is active against taxane-resistant cell lines and is synergistic with 5-FU in vitro and in vivo. Two translational studies have been conducted: a Phase IB study of IDB in combination with capecitabine (CAP) in patients with advanced solid tumors, and mathematical modeling applying Norton-Simon models to breast carcinoma MX-1 xenografts to further develop Phase II dose. Methods: IDB is administered continuously starting at 400 mg BID. CAP is administered for 2 weeks with 1 week rest, starting at 875 mg/m2 BID. IDB and CAP are escalated to MTD: IDB 600 mg BID & CAP 1000 mg/m2 BID. Efficacy is evaluated every 9 weeks using RECIST. In the xenograft model indibulin is administered at dose levels from 12 to 28.7 mg/kg/day to nude mice carrying MX-1 breast carcinoma. Tumor growth is analyzed using a Gompertzian-type growth model to determine via calculus of variations the optimal schedule to maximize the efficacy/toxicity ratio. Results: To date, 7 patients have been treated and are evaluable for safety. Median age 62 yrs; ECOG ≤1; median prior therapies 3. Four patients are evaluable for efficacy and all have stable disease (3 for 6 cycles, 1 for 3 cycles). AEs include hand-and-foot syndrome (CAP), fatigue, vomiting, anorexia, and headache. Neither DLTs nor grade ≥3 AEs have been observed. In MX-1 xenografts, indibulin demonstrates linear dose-efficacy relationship over the range of 12 to 22 mg/kg. At all dose levels the first 5 days of administration are associated with a rapid accumulation of anticancer effect with lesser effects over the next 5 days to a peak of efficacy at day 10 Conclusions: IDB + CAP is well tolerated, without neurotoxicity. There is preliminary evidence of clinical activity even with this sub-optimal, continuous schedule of IDB. Formal analyses suggest that an intermittent schedule could optimize efficacy, minimize acquired resistance and allow for host recovery from drug-induced toxicity. Pre- clinical evaluation in a breast cancer model supports an intermittent dosing schedule to further increase the activity of IDB. [Table: see text]

Phase I Study of IMGN901 in Patients with Relapsed and Relapsed/Refractory CD56-Positive Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3689-3689 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Mecide Gharibo ◽  
Sundar Jagannath ◽  
Nikhil C. Munshi ◽  
Kenneth C Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Minor Response

Abstract Background: IMGN901 (huN901-DM1) is a novel conjugate of the cytotoxic maytansinoid, DM1, with the humanized CD56-binding monoclonal antibody, N901. Once bound to CD56 on a cancer cell, the conjugate is internalized and releases DM1. About 70% of multiple myeloma (MM) cases have surface expression of CD56. Preclinical investigations demonstrated significant in vitro and in vivo anti-myeloma activity of IMGN901. Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of increasing doses of IMGN901 given for MM on a weekly schedule. Methods: Patients with relapsed or relapsed/refractory MM who have failed at least one prior therapy and have CD56-expressing MM received a single IV infusion of IMGN901 on 2 consecutive weeks every 3 weeks. Patients are enrolled in cohorts of 3 at each dose level, with DLT triggering cohort expansion. Results: Eighteen patients have received IMGN901 to date in this study - 3 patients each at 40, 60, 75, 90, 112, and 140 mg/m2/week. One patient experienced a DLT (grade 3 fatigue) on 140 mg/m2/week, and this cohort is being expanded to enroll up to 6 patients. No patients have experienced serious hypersensitivity reactions or evidence of presence of humoral responses against the huN901 antibody component (HAHA) or against the DM1 component (HADA). Preliminary PK results indicate an approximately linear relationship between dosing and observed maximal serum concentration. A confirmed minor response (MR) was documented in 3 heavily pretreated patients (1 patient each at 60, 90, and 112 mg/m2/week) using the European Bone Marrow Transplant criteria. Durable stable disease was reported at doses of 60, 90, 112, and 140 mg/m2/week. Of the 18 patients treated in the study, eight patients remained on treatment with IMGN901 for at least 15 weeks, five of these 8 patients remained on treatment for at least 24 weeks, and two of these 5 patients remained on treatment for at least 42 weeks. This phase I study provides preliminary evidence of safety as well as clinical activity of IMGN901 in patients with CD56-positive MM who have failed established MM treatments. Updated results of this ongoing study will be presented.

A phase I study of oral darinaparsin in patients (pts) with advanced solid tumors (AST).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13040-e13040
Author(s):  
Luis H. Camacho ◽  
Neil N. Senzer ◽  
Wael A. Harb ◽  
John A Barrett ◽  
Christopher Charles Korth ◽  
...  
Keyword(s):  
Oral Formulation ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Drug Discontinuation ◽  
Serum Trough ◽  
Grade 3 ◽  
Ecog Ps ◽  
Trough Levels

e13040 Background: Darinaparsin [Zinapar, ZIO-101(S-dimethylarsino-glutathione)], is a novel organic arsenic compound with in vitro and in vivo anticancer activity in tumor cell lines resistant to arsenic trioxide. An oral formulation is now available. Methods: This study used a 3+3 escalating design, dosing orally for 21 days followed by 7 days off (28 day cycle). Pts with AST refractory to standard therapy, ECOG performance score (PS) ≤ 2 and adequate organ function were treated. Study objectives were safety profile evaluation, pharmacokinetics (PK) and preliminary activity of oral darinaparsin. CTCAE v. 4.0 and RECIST 1.1 were used. Results: A total of 10 pts (8 males, 2 females), with ECOG PS 0=2, 1=8, mean age of 71 years (range: 60-81), median of prior therapies 3 (range: 1-4) were treated. A median of 2 cycles of darinaparsin was administered (range: 1-6). Dose limiting toxicities (DLT) were confusion (n=1; 400 mg), cognitive disturbance (n=1; 400 mg) and encephalopathic syndrome (n=1; 300 mg), reversible with drug discontinuation. The highest tolerable dose was 300 mg per day. Most frequent AEs were: hypokalemia, nausea (40% each), fatigue (30%), anemia, diarrhea, hypophosphatemia, pneumonia, vomiting (20% each). Most frequent grade ≥3 AEs were: hypokalemia, hypophosphatemia (20% each). Best overall response was stable disease (at 2 cycles), observed in 5 pts: adenocarcinoma of colon (2 pts), chordoma, adenocarcinoma of small bowel and carcinoma of tongue. PK analysis of 400 mg cohort (n=4) and 300 mg cohort (n=6) resulted in Tmax at 9 hr post treatment and Cmax slightly greater than dose proportional (p<0.05). Steady-state trough levels were achieved on or before Day 5. Approximately 40 % greater Cmax was observed on D15 compared to D1 for the 300 mg cohort (p<0.05) while unchanged at 400 mg. DLTs were observed when duration of exposure was more than 7 days and serum trough levels were 800 ng/ml or above. Conclusions: Oral darinaparsin is well tolerated at the dosage of 300 mg per day for 21days in a 28 day cycle in pts with AST. Preliminary evidence of clinical activity and a predictable PK profile justify further evaluation of darinaparsin in selected indications.

HM1.24/CD317-directed immunotoxin to eliminate malignant plasma cells in vitro and in vivo.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8604-8604
Author(s):  
Martin Gramatzki ◽  
Matthias Staudinger ◽  
Pia Glorius ◽  
Katja Klausz ◽  
Christian Kellner ◽  
...  
Keyword(s):  
Mouse Model ◽  
Plasma Cells ◽  
Xenograft Model ◽  
Clinical Activity ◽  
Target Structure ◽  
Single Chain ◽  
Pseudomonas Exotoxin A ◽  
Single Chain Fv

8604 Background: Targeted immunotherapy, based on antibodies against tumor-associated antigens, is a promising approach for the treatment of multiple myeloma (MM). Recently, antibody-based strategies delivering a toxic payload have documented impressive clinical activity in hematological malignancies. In particular, surface molecules overexpressed on malignant plasma cells and efficiently internalized represent promising targets for developing myeloma-directed immunoconstructs. Here, the identification of CD317 (HM1.24) as a potent target structure and the characterization of a novel CD317-directed single-chain immunotoxin, HM1.24-ETA', is described. Methods: Using a novel screening tool, a panel of antibodies against MM-associated antigens was evaluated for their ability to mediate antigen-dependent delivery of a truncated version of Pseudomonas exotoxin A (ETA’) to MM cells. HM1.24-ETA' was generated by genetic fusion of a CD317-specific single-chain Fv antibody and ETA'. The anti-myeloma activity of the E. coli-expressed immunotoxin was evaluated in vitro and in a xenograft mouse model. Results: By screening a panel of antibodies including CD38, CS1, IL-6R, CD138 and CD317, CD317 was identified as a suitable receptor to deliver ETA’ to MM cells. The subsequently designed recombinant HM1.24-ETA' immunotoxin efficiently inhibited growth of MM cell lines with halfmaximal growth inhibition at concentrations of less than 1 nM. Antigen-specific MM cell killing occurred via induction of apoptosis. The proliferation of IL-6 dependent INA-6 cells was completely inhibited by HM1.24-ETA' even in the presence of bone marrow stromal cells that otherwise strongly support tumor cell growth. Importantly, HM1.24-ETA' strongly triggered apoptosis (up to 80%) in freshly isolated tumor cells from 7 out of 7 MM patients. In a xenograft SCID mouse model, establishment of INA-6 plasma cell tumors was efficiently abrogated by treatment with HM1.24-ETA' immunotoxin (p < 0.04). Conclusions: The HM1.24-ETA' immunotoxin in vitro and in the preclinical xenograft model in vivo demonstrates that the CD317 antigen may represent a promising target structure for immunotherapy of MM using immunoconjugates with toxic payloads.

The role of enzalutamide-induced hyperactive Jak2-Stat5 feed-forward signaling loop on enzalutamide-resistant prostate cancer growth and as a therapeutic target for second-line treatment.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 221-221 ◽  
Author(s):  
Vindhya Udhane ◽  
Cristina Maranto ◽  
David Hoang ◽  
Andrew Erickson ◽  
Savita Devi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Acquired Resistance ◽  
Clinical Activity ◽  
Line Treatment ◽  
Second Line ◽  
Potent Inducer ◽  
Feed Forward

221 Background: Androgen targeted therapy remains the mainstay for advanced prostate cancer (PC). Second-generation androgen receptor (AR) antagonist, enzalutamide (ENZ), re-targets persistent AR activity in castrate-resistant (CR) PC tumors, and is approved for CRPC. Despite initial clinical activity, acquired resistance to ENZ arises rapidly and most patients succumb to PC. Mechanisms underlying resistance to ENZ are incompletely understood. Prior work has established Stat5 as a potent inducer of PC growth. Here, we investigated the significance of Jak2-Stat5 signaling in ENZ-resistant growth of PC. Methods: Levels of Jak2 and Stat5 activation in PC cells, tumors and patient samples were evaluated by immunohistochemistry, 3D tumor explant cultures and western blotting. Jak2 and Stat5 were inhibited by lentiviral (expression of) shRNA or pharmacologically. Levels of mRNA were assessed by QPCR and gene expression profiling. Results: ENZ induced a robust increase in Stat5 activation in PC cells in vitro, in xenograft tumors in vivo and in patient-derived PCs during ENZ treatment. Mechanistically, ENZ activation of Stat5 involves a positive feed-forward mechanism where ENZ-liganded AR induces rapid and sustained Jak2 phosphorylation in PC cells through a process involving Jak2-specific phosphatases. This results in a formation of a positive feed-forward loop in PC where activated Stat5 induces Jak2 mRNA and protein levels in PC. We showed that active Stat5 increased viability of PC cells during ENZ treatment and, at the same time, inhibition of Stat5 as a second-line treatment induced excessive death of PC cells surviving ENZ treatment. Importantly, pharmacological Stat5 blockade inhibited CR growth of PC xenograft tumors after ENZ resistance developed. Conclusions: Collectively, this work introduces a novel concept for a pivotal role of Jak2-Stat5 signaling in mediating resistance of PC to ENZ. Pharmacological Jak2-Stat5 inhibition may provide efficacious therapy in advanced PC in combination with ENZ or after ENZ fails.

Pre-Clinical Activity of Amino-Alcohol Dimeric Naphthoquinones as Potential Therapeutics for Acute Myeloid Leukemia

2021 ◽  
Vol 21 ◽  
Author(s):  
Dana Ferraris ◽  
Rena Lapidus ◽  
Phuc Truong ◽  
Dominique Bollino ◽  
Brandon Carter-Cooper ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Amino Alcohol ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Xenograft Model ◽  
Clinical Activity ◽  
Lead Compound ◽  
Acute Myeloid

Background: The clinical outcomes of patients with acute myeloid leukemia (AML) remain unsatisfactory, therefore the development of more efficacious and better-tolerated therapy for AML is critical. We have previously reported the anti-leukemic activity of synthetic halohydroxyl dimeric naphthoquinones (BiQ) and aziridinyl BiQ. Objective: This study aimed to improve the potency and bioavailability of BiQ compounds and investigate the anti-leukemic activity of the lead compound in vitro and in a human AML xenograft mouse model. Methods: We designed, synthesized, and performed structure-activity relationship of several rationally designed BiQ analogues that possess amino alcohol functional groups on the naphthoquinone core rings. The compounds were screened for anti-leukemic activity and the mechanism as well as in vivo tolerability and efficacy of our lead compound was investigated. Results: We report that a dimeric naphthoquinone (designated BaltBiQ) demonstrated potent nanomolar anti-leukemic activity in AML cell lines. BaltBiQ treatment resulted in the generation of reactive oxygen species, induction of DNA damage, and inhibition of indoleamine dioxygenase 1. Although BaltBiQ was tolerated well in vivo, it did not significantly improve survival as a single agent, but in combination with the specific Bcl-2 inhibitor, Venetoclax, tumor growth was significantly inhibited compared to untreated mice. Conclusion: We synthesized a novel amino alcohol dimeric naphthoquinone, investigated its main mechanisms of action, reported its in vitro anti-AML cytotoxic activity, and showed its in vivo promising activity combined with a clinically available Bcl-2 inhibitor in a patient-derived xenograft model of AML.

scholarly journals Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Jacopo Gavini ◽  
Noëlle Dommann ◽  
Manuel O. Jakob ◽  
Adrian Keogh ◽  
Laure C. Bouchez ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Antitumor Effect ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Resistance Mechanisms ◽  
Chemotherapeutic Agents ◽  
Anti Cancer

Abstract Lysosomal sequestration of anti-cancer compounds reduces drug availability at intracellular target sites, thereby limiting drug-sensitivity and inducing chemoresistance. For hepatocellular carcinoma (HCC), sorafenib (SF) is the first line systemic treatment, as well as a simultaneous activator of autophagy-induced drug resistance. The purpose of this study is to elucidate how combination therapy with the FDA-approved photosensitizer verteporfin (VP) can potentiate the antitumor effect of SF, overcoming its acquired resistance mechanisms. HCC cell lines and patient-derived in vitro and in vivo preclinical models were used to identify the molecular mechanism of action of VP alone and in combination with SF. We demonstrate that SF is lysosomotropic and increases the total number of lysosomes in HCC cells and patient-derived xenograft model. Contrary to the effect on lysosomal stability by SF, VP is not only sequestered in lysosomes, but induces lysosomal pH alkalinization, lysosomal membrane permeabilization (LMP) and tumor-selective proteotoxicity. In combination, VP-induced LMP potentiates the antitumor effect of SF, further decreasing tumor proliferation and progression in HCC cell lines and patient-derived samples in vitro and in vivo. Our data suggest that combination of lysosome-targeting compounds, such as VP, in combination with already approved chemotherapeutic agents could open a new avenue to overcome chemo-insensitivity caused by passive lysosomal sequestration of anti-cancer drugs in the context of HCC.

scholarly journals Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
S Michael Rothenberg ◽  
Kyle Concannon ◽  
Sarah Cullen ◽  
Gaylor Boulay ◽  
Alexa B Turke ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Tumor Regression ◽  
Acquired Resistance ◽  
Ectopic Expression ◽  
Growth Factor Signaling ◽  
Drug Induced ◽  
Mutant Egfr

Treatment of EGFR-mutant lung cancer with erlotinib results in dramatic tumor regression but it is invariably followed by drug resistance. In characterizing early transcriptional changes following drug treatment of mutant EGFR-addicted cells, we identified the stem cell transcriptional regulator SOX2 as being rapidly and specifically induced, both in vitro and in vivo. Suppression of SOX2 sensitizes cells to erlotinib-mediated apoptosis, ultimately decreasing the emergence of acquired resistance, whereas its ectopic expression reduces drug-induced cell death. We show that erlotinib relieves EGFR-dependent suppression of FOXO6, leading to its induction of SOX2, which in turn represses the pro-apoptotic BH3-only genes BIM and BMF. Together, these observations point to a physiological feedback mechanism that attenuates oncogene addiction-mediated cell death associated with the withdrawal of growth factor signaling and may therefore contribute to the development of resistance.

scholarly journals Clarithromycin synergizes with cisplatin to inhibit ovarian cancer growth in vitro and in vivo

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Bo Zhou ◽  
Meng Xia ◽  
Bin Wang ◽  
Niresh Thapa ◽  
Lijuan Gan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Annexin V ◽  
Therapy Resistance ◽  
Tumor Xenograft ◽  
Cancer Cell Growth ◽  
Cisplatin Therapy

Abstract Background Cisplatin-based chemotherapy is the first-line treatment for ovarian cancer. However, acquired resistance to cisplatin treatment often occurs in epithelial ovarian cancer, and effective and practical methods for overcoming this obstacle are urgently needed. The study aimed to demonstrate the synergistic effect of clarithromycin (CAM) with cisplatin to inhibit ovarian carcinoma cells growth in vitro and in vivo. Results We performed CCK-8 assay to detect apoptosis rates in response to CAM alone or in combination with cisplatin, which were further confirmed by Annexin V and PI staining methods and western blotting. Mechanistically, CAM could reduce endogenous antioxidant enzyme expression and increase the levels of reactive oxygen species (ROS) to augment the cytotoxic effect of cisplatin. Meanwhile, a tumor xenograft model in athymic BALB/c-nude mice demonstrated that CAM combined with cisplatin resulted in reduced tumor growth and weight compared with cisplatin alone. Conclusion Collectively, our results indicate that CAM works synergistically with cisplatin to inhibit ovarian cancer cell growth, which may be manipulated by a ROS-mediated mechanism that enhances cisplatin therapy, and offers a novel strategy for overcoming cisplatin therapy resistance.

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