Investigational New Drugs

  1573-0646

  0167-6997

 

Cơ quản chủ quản:  SPRINGER , Kluwer Academic Publishers

Lĩnh vực:
OncologyPharmacology (medical)Pharmacology

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Các bài báo tiêu biểu

Pre-operative chemoradiation followed by post-operative adjuvant therapy with tetrathiomolybdate, a novel copper chelator, for patients with resectable esophageal cancer
Tập 31 - Trang 435-442 - 2012
Bryan J. Schneider, Julia Shin-Jung Lee, James A. Hayman, Andrew C. Chang, Mark B. Orringer, Allan Pickens, Charlie C. Pan, Sofia D. Merajver, Susan G. Urba
Introduction This phase II trial investigated chemoradiation followed by surgery and 2 years of adjuvant tetrathiomolybdate (TM) for resectable esophageal cancer. Methods Patients with resectable, locally advanced esophageal cancer received neoadjuvant cisplatin 60 mg/m2 (days 1 and 22), paclitaxel 60 mg/m2 (days 1, 8, 15, and 22), and 45 Gy hyperfractionated radiotherapy for 3 weeks followed by transhiatal esophagectomy. TM 20 mg PO QD was started 4 weeks post-op, and continued for 2 years to maintain the ceruloplasmin level between 5 and 15 mg/dl. Results Sixty-nine patients were enrolled (median age, 60 years). Sixty-six patients underwent surgery and 61 patients had a complete resection. Histologic complete response rate was 10 %. Twenty-one patients did not receive TM (metastases noted in the peri-operative period, prolonged post-operative recovery time, or patient refusal). Forty-eight patients started TM; 14 completed 24 months of treatment, 11 completed 10–18 months, 15 completed 2–8 months, and 8 completed ≤1 month. Twenty-seven patients had disease recurrence. With a median follow-up of 55 months, 25 patients were alive without disease, 1 was alive with disease, and 43 have died. Three-year recurrence-free survival was 44 % (95 % CI, 32–55 %) and the three-year overall survival was 45 % (95 % CI 33–56 %). Conclusions TM is an antiangiogenic agent that is well tolerated in the adjuvant setting. Disease-free survival and overall survival are promising when compared to historical controls treated at our institution with a similar regimen that did not include TM. However, the challenges associated with prolonged administration limit further investigation.
Comparative in vitro cytotoxicity of cyclophosphamide, its major active metabolites and the new oxazaphosphorine ASTA Z 7557 (INN mafosfamide)
Tập 2 Số 2 - Trang 141-148 - 1984
David S. Alberts, Janine G. Einspahr, Robert F. Struck, Gary S. Bignami, Lai Sang Young, Earl A. Surwit, Sydney E. Salmon
Phase II trial of piroxantrone for advanced or metastatic soft tissue sarcomas
- 1993
Mark M. Zalupski, Jacqueline Benedetti, Stanley P. Balcerzak, Laura F. Hutchins, Robert J. Belt, Alexander Hantel, John Wendall Goodwin
Piroxantrone is an anthrapyrazole compound undergoing phase II testing in a variety of diseases. The anthrapyrazoles are a series of compounds synthesized with the intent of maintaining the broad antitumor activity of anthracyclines, but with lessened cardiac toxicity. The Southwest Oncology Group (SWOG) conducted a phase II trial of piroxantrone in advanced soft tissue sarcoma. Treatment consisted of piroxantrone 150 mg/M2 administered intravenously over 1 hour every 21 days. Twenty-five eligible patients were registered to the trial. Twenty-three patients received treatment and are fully evaluable for response and toxicity. Two partial responses were seen for an overall response rate of 9% (95% confidence limit 1%–28%). Abnormal cardiac ejection fraction occurred in five patients, and fatal congestive heart failure developed in one patient on study. Toxicities other than cardiac were tolerable. Based on the observed response rate and cardiac toxicity, further trials of piroxantrone in the treatment of soft tissue sarcoma do not appear warranted.
Phase I Study of Irofulven (MGI 114), an Acylfulvene Illudin Analog, in Patients with Acute Leukemia
Tập 19 - Trang 13-20 - 2001
Francis Giles, Jorge Cortes, Guillermo Garcia-Manero, Stephen Kornblau, Elihu Estey, Monica Kwari, Anthony Murgo, Hagop Kantarjian
Irofulven (MGI 114, 6-hydroxymethylacylfulvene, HMAF)is a semisynthetic illudin analog with broad in vitroanti-neoplastic activity. In this leukemia phase I study, weinvestigated the toxicity profile and activity of Irofulven inpatients with primary refractory or relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), ormyelodysplastic syndromes (MDS). Irofulven was given as anintravenous infusion over five minutes daily for five days.The starting dose was 10 mg/m2/day (50mg/m2/course). Courses were scheduled to be givenevery 3-4 weeks according to toxicity and antileukemicefficacy. Twenty patients {AML: 17 patients; MDS: onepatient; ALL: one patient; mixed lineage acute leukemia: onepatient} were treated. Nausea, vomiting, hepatic dysfunction,weakness, renal dysfunction, and pulmonary edema were doselimiting toxicities, occurring in two of five patientstreated at 20 mg/m2/day and two of three patientstreated at 12.5 mg/m2/day. The MTD was defined as10 mg/m2/day for five days. One patient withprimary resistant AML achieved complete remission. Proposedphase II studies will further define the activity of Irofulvenin patients with better prognosis AML and in otherhematological malignancies, both as a single agent and incombination regimens, particularly with topoisomerase 1inhibitors.
A tumor-selective adenoviral vector platform induces transient antiphospholipid antibodies, without increased risk of thrombosis, in phase 1 clinical studies
- 2023
Danny N. Khalil, Isabel Prieto González-Albo, Lee Rosen, Tom Lillie, Andrea Stacey, Lola Parfitt, Gerald A. Soff
Tumor-selective viruses are a novel therapeutic approach for treating cancer. Tumor-Specific Immuno Gene Therapy (T-SIGn) vectors are tumor-selective adenoviral vectors designed to express immunomodulatory transgenes. Prolonged activated partial thromboplastin time (aPTT), associated with the presence of antiphospholipid antibodies (aPL), has been observed in patients with viral infections, and following administration of adenovirus-based medicines. aPL may be detected as lupus anticoagulant (LA), anti-cardiolipin (aCL) and/or anti-beta 2 glycoprotein antibodies (aβ2GPI). No subtype alone is definitive for development of clinical sequalae, however, patients who are ‘triple positive’ have a greater thrombotic risk. Additionally, isolated aCL and aβ2GPI IgM do not appear to add value in thrombotic association to aPL positivity, rather IgG subtypes must also be present to confer an increased risk. Here we report induction of prolonged aPTT and aPL in patients from eight Phase 1 studies who were treated with adenoviral vectors (n = 204). Prolonged aPTT (≥ Grade 2) was observed in 42% of patients, with a peak at 2–3 weeks post-treatment and resolution within ~ 2 months. Among patients with aPTT prolongation, LA, but not aCL IgG nor aβ2GPI IgG, was observed. The transience of the prolongation and discordance between positive LA and negative aCL/aβ2GPI IgG assays is not typical of a prothrombotic state. Among the patients with prolonged aPTT there was no evidence of an increased rate of thrombosis. These findings elucidate the relationship between viral exposure and aPL in the context of clinical trials. They suggest a framework in which hematologic changes can be monitored in patients receiving similar treatments. Clinical trial registration: NCT02028442, NCT02636036, NCT02028117, NCT03852511, NCT04053283, NCT05165433, NCT04830592, NCT05043714.
Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors
Tập 25 - Trang 131-138 - 2006
Luis H. Camacho, Jon Olson, William P. Tong, Charles W. Young, David R. Spriggs, Mark G. Malkin
Background: Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown. Methods: We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60–360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each. Results: Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA ≥1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively. Conclusions: Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended.
Phase II evaluation of dianhydrogalactitol in the treatment of advanced non-squamous cervical carcinoma
Tập 2 - Trang 331-333 - 1984
Frederick B. Stehman, John A. Blessing, Howard D. Homesley, John L. Currie, Edgardo L. Yordan
In an on-going Phase II evaluation, dianhydrogalactitol (NSC 132313) was administered intravenously to 28 patients with advanced or recurrent non-squamous cell carcinoma of the cervix. The initial dosage was 60 mg/m2/wk with escalation to 75 mg/m2/wk if there were no adverse effects. Twenty-seven patients were evaluable for toxicity and response. There was one complete response and one partial response. Adverse effects were not infrequent but tolerable.
Cardamonin, a natural chalcone, reduces 5-fluorouracil resistance of gastric cancer cells through targeting Wnt/β-catenin signal pathway
Tập 38 - Trang 329-339 - 2019
Gaochao Hou, Xiang Yuan, Yi Li, Gaoyu Hou, Xianli Liu
Objectives Cardamonin (CD), an active chalconoid, has been extensively studied in a wide variety of human tumors. However, the effects and underlying mechanism of cardamonin on 5-fluorouracil (5-FU)-resistant gastric cancer (GC) remain largely unclear. This study aimed to investigate the antitumor effects of cardamonin on 5-FU-resistant GC cells and explore the molecular mechanisms underlying its therapeutic potential. Methods The antitumor activities of cardamonin, 5-FU and their combination against BGC-823 and BGC-823/5-FU cells were determined using cytotoxicity assay, flow cytometry-based cell cycle analysis and Annexin V apoptosis assay. The effect of cardamonin on P-glycoprotein activity was assessed by Rh123 uptake assay. Real-time PCR, Western blotting and Co-immunoprecipitation analysis were carried out to assess the inhibition of Wnt/β-catenin signaling pathway. A xenograft mouse model was established using BALB/c nude mice to examine the combinatorial effects of cardamonin and 5-FU on tumor growth. Results Our data provided the first demonstration that cardamonin significantly enhanced the chemosensitivity of 5-FU in GC cells via suppression of Wnt/β-catenin signaling pathway. Additionally, the combination of cardamonin and 5-FU might result in the apoptosis and cell cycle arrest of BGC-823/5-FU cells, accompanied by the downregulated expression levels of P-glycoprotein, β-catenin and TCF4. More importantly, our results demonstrated that cardamonin specifically disrupted the formation of β-catenin/TCF4 complex, leading to TCF4-mediated transcriptional activation in 5-FU-resistant GC cells. Besides, through a xenograft mouse model, co-administration of cardamonin and 5-FU significantly retarded tumor growth in vivo, thus, confirming our in vitro findings. Conclusions Overall, this study revealed that cotreatment of cardamonin and 5-FU could strongly potentiate the antitumor activity of 5-FU, and put forth cardamonin as a rational therapeutic strategy for drug-resistant GC treatment.
In vivo and in vitro assessment of the action of SN 28049, a benzonaphthyridine derivative targeting topoisomerase II, on the murine Colon 38 carcinoma
Tập 29 - Trang 1504-1510 - 2010
Ying Yi Chen, Graeme J. Finlay, James A. Kirker, Elaine S. Marshall, Emma Richardson, Bruce C. Baguley
Aim: SN 28049 (N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide) is a new DNA binding drug that targets topoisomerase II. SN 28049 is curative against the murine Colon 38 adenocarcinoma (CT38) while etoposide, another topoisomerase II-directed drug, shows minimal activity; we investigated the basis for this difference in vivo and in vitro. Methods: Colon 38 tumours were grown in C57Bl mice and in immunodeficient mice. Tumour sections were examined by staining and TUNEL assays. A new cell line (Co-38P) derived from the in vivo tumour was developed and responses were analysed using flow cytometry. Results: Both SN 28049 and etoposide induced similar tumour histological changes, reducing mitotic index and increasing apoptotic index 8 h after administration. At later times however, SN 28049-treated tumours showed further progressive morphological changes while etoposide-treated tumours reverted to their original growth characteristics. The effects of SN 28049 on tumour growth were delayed and attenuated when Colon 38 tumours were grown in immunodeficient mice. SN 28049 and etoposide both induced dose-dependent increases of γ-phosphorylation of histone H2AX and cell cycle perturbation of the Co-38P cell line, indicative of DNA damage, although SN 28049 had 30-fold higher activity. Following 1-hour drug exposure of Co-38P cells, SN 28049 was more effective that etoposide in inducing persistent cycle arrest for the same degree of DNA damage. Conclusion: The superior antitumour activity of SN 28049 may result from its ability to induce long term cycle arrest. Host immune responses contribute to the curative activity of SN 28049 and this could result from the induction of cycle arrest.
Phase I and pharmacokinetic study of dacomitinib (PF-00299804), an oral irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases, in Japanese patients with advanced solid tumors
Tập 30 - Trang 2352-2363 - 2012
Toshiaki Takahashi, Narikazu Boku, Haruyasu Murakami, Tateaki Naito, Asuka Tsuya, Yukiko Nakamura, Akira Ono, Nozomu Machida, Kentaro Yamazaki, Junichiro Watanabe, Ana Ruiz-Garcia, Keiji Imai, Emiko Ohki, Nobuyuki Yamamoto
Background Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. Methods This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity. Results Thirteen patients were assigned to the three dose levels (15 mg cohort: n = 3; 30 mg cohort: n = 3; 45 mg cohort: n = 7) according to a traditional ‘3 + 3’ design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease. Conclusions Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors.