Open-label extension study of the RNAi therapeutic ALN-VSP02 in cancer patients responding to therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3062-3062 ◽  
Author(s):  
Maria Alsina ◽  
Josep Tabernero ◽  
Geoffrey Shapiro ◽  
Howard Burris ◽  
Jeffrey R. Infante ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Adverse Events ◽  
Phase I ◽  
Cell Carcinoma ◽  
Phase I Trial ◽  
Tumor Regression ◽  
Average Length ◽  
Phase 1 ◽  
Extension Study ◽  
Phase Ii Trials

3062 Background: ALN-VSP02 is an RNA interference (RNAi) therapeutic comprised of lipid nanoparticle-formulated small interfering RNAs targeting vascular endothelial growth factor (VEGF)-A and kinesin spindle protein (KSP). In a phase 1 trial, ALN-VSP02 administered as an iv infusion q2 wks was well-tolerated and showed evidence of anti-VEGF pharmacology and antitumor activity. Methods: Patients treated on the phase I trial with stable disease (SD) or better after 4 months (8 doses) were eligible to continue on an extension study until disease progression. Main objectives included continued evaluation of safety/tolerability and assessment of disease response. Results: Seven of 37 patients (18.9%) evaluable for response went onto the extension study, including 1 of 7 (14.2%) at 0.4 mg/kg, 2 of 5 (40%) at 0.7 mg/kg, and 4 of 11 (36.3%) at 1.0 mg/kg. All had progressed after one or more prior therapies. Tumor types included head and neck squamous cell carcinoma, angiosarcoma, endometrial cancer, renal cell carcinoma (RCC, N=2), and pancreatic neuroendocrine tumor (PNET, N=2). At the time of enrollment, 6 had SD and one (endometrial cancer with multiple liver metastases) had an unconfirmed partial response (PR). The average length of time on treatment (including phase I and extension studies) was 9.5 months (range 5-19). As of January 2012, 3 patients remain on study, including the endometrial cancer patient with an ongoing PR who has had >80% tumor regression after 19 months of treatment at 0.7 mg/kg and two patients with RCC and PNET with continued SD after nearly 1 year of treatment at 1.0 mg/kg. The other patients with RCC and PNET at 1.0 mg/kg with SD came off after 8.5 and 5.5 months, respectively, for adverse events that included fatigue or elevated alkaline phosphatase. A decrease in spleen volume, likely an on-target effect and not associated with any adverse events, occurred to a greater degree on the extension study than on the phase I trial and was most pronounced in patients receiving ≥ 12 doses. Conclusions: ALN-VSP02 has preliminary activity against endometrial cancer, RCC and PNET and a favorable safety profile that permits chronic dosing. Phase II trials are warranted in these and other VEGF-overexpressing tumors.

Intrathecal Mafosfamide: A Preclinical Pharmacology and Phase I Trial

2005 ◽  
Vol 23 (7) ◽  
pp. 1555-1563 ◽  
Author(s):  
Susan M. Blaney ◽  
Frank M. Balis ◽  
Stacey Berg ◽  
Carola A.S. Arndt ◽  
Richard Heideman ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Neoplastic Meningitis ◽  
In Vitro Cytotoxicity ◽  
Pharmacokinetic Studies ◽  
Preclinical Studies ◽  
Phase Ii Trials ◽  
Cytotoxicity Studies

Purpose Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

scholarly journals Phase I Trial of Sequential Low-Dose 5-Aza-2′-Deoxycytidine Plus High-Dose Intravenous Bolus Interleukin-2 in Patients with Melanoma or Renal Cell Carcinoma

2006 ◽  
Vol 12 (15) ◽  
pp. 4619-4627 ◽  
Author(s):  
Jared A. Gollob ◽  
Catherine J. Sciambi ◽  
Bercedis L. Peterson ◽  
Tina Richmond ◽  
Monica Thoreson ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Phase I ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Phase I Trial ◽  
Low Dose ◽  
Interleukin 2 ◽  
High Dose ◽  
Intravenous Bolus

A phase I trial evaluating NBTXR3 activated by radiotherapy in combination with nivolumab or pembrolizumab in patients with advanced cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2590-2590
Author(s):  
Colette Shen ◽  
Jessica M. Frakes ◽  
Jiaxin Niu ◽  
Ari Rosenberg ◽  
Jared Weiss ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Kidney Injury ◽  
Complete Response ◽  
Intratumoral Injection ◽  
Primary Objective ◽  
Open Label

2590 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1 are an effective treatment for a variety of cancers. However, the majority of patients (pts) exhibit resistance to ICIs. Overcoming this resistance represents a major challenge in immuno-oncology. Emerging evidence suggests radiation therapy (RT) produces an immunomodulatory effect that may act synergistically with ICIs. However, RT dose and ultimate efficacy are limited by toxicity to surrounding healthy tissues. NBTXR3, a novel radioenhancer administered by direct intratumoral injection (ITI), is designed at the nanoscale to increase RT dose deposit within tumor cells and subsequent tumor cell killing, without increasing toxicity to surrounding healthy tissue. Preclinical data suggest NBTXR3/RT can trigger a local and systemic anti-tumor immune response and overcome anti-PD-1 resistance. NBTXR3/RT combined with anti-PD-1 may prime the immune system to increase the proportion of ICI responders, or convert ICI non-responders to responders. Methods: This is a multicenter, open-label, phase I trial [NCT03589339] to evaluate NBTXR3/RT/anti-PD-1 in 3 cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to HN re-irradiation, and metastases from any primary cancer eligible for anti-PD-1 (nivolumab or pembrolizumab) treatment specifically localized in the lung (2) or liver (3), respectively. Stereotactic body RT (SBRT) is delivered at tumor-site selective doses per standard practice. The primary objective is NBTXR3/RT/anti-PD-1 recommended phase 2 dose in each cohort. Secondary objectives are anti-tumor response (objective response rate), safety and feasibility of NBTXR3 injection. Results: Nine pts have been treated: 3 HNSCC, 4 lung, 2 liver. 7/9 pts were anti-PD-1 non-responders. Overall tumor regression was observed in 8/9 pts. NBTXR3/RT/anti-PD-1 resulted in tumor regression in 6/7 pts who had progressed on prior anti-PD-1. A complete response in the injected lymph node lasting over 1 year was observed in 1 anti-PD-1 naïve pt. 2 SAEs related to anti-PD-1 and possibly related to NBTXR3 (G5 pneumonitis, G4 hyperglycemia) were observed in 1 anti-PD-1 naïve HNSCC pt and considered DLTs. This pt also experienced 2 other SAEs related to anti-PD-1 (G4 diabetic ketoacidosis, G4 acute kidney injury). SBRT-related safety profile was as expected. Updated results will be presented. Conclusions: Data from this first-in-human phase I trial evaluating NBTXR3/RT/anti-PD-1 in pts with advanced cancers, show NBTXR3 ITI is feasible and well-tolerated. NBTXR3/RT/anti-PD-1 demonstrated promising signs of efficacy. Of particular interest, NBTXR3/RT can overcome ICI resistance in pts having progressed on prior anti-PD-1, supporting further development of NBTXR3 in combination with anti-PD-1 as well as other ICIs. Clinical trial information: NCT03589339.

scholarly journals A phase I trial of intermittent high-dose α-interferon and dexamethasone in metastatic renal cell carcinoma

1995 ◽  
Vol 6 (9) ◽  
pp. 911-914 ◽  
Author(s):  
R. Amato ◽  
C. Meyers ◽  
J. Ellerhorst ◽  
L. Finn ◽  
R. Kilbourn ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Phase I ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Phase I Trial ◽  
High Dose

Phase i Trial with Peptichemio

1979 ◽  
Vol 65 (1) ◽  
pp. 99-104
Author(s):  
Lucien Israel ◽  
Maurice Kohn ◽  
Alain Depierre ◽  
Jacques Aguilera
Keyword(s):  
Drug Treatment ◽  
Phase I ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Hematological Toxicity ◽  
Cytostatic Drug ◽  
Cytostatic Drugs ◽  
Phase Ii Trials ◽  
Repeated Administrations ◽  
Infusion Fluid

Thirty-two patients with tumor progression, even after conventional cytostatic drug treatment, were treated with peptichemio, with increasing doses for groups of 4 patients. The maximum tolerated dose (with minimum hematological toxicity and without any other evident toxicity) with repeated administrations, was 1.2 mg/kg twice weekly. The recommended doses for phase II trials are, as shown by the detailed analysis of the results, 0.9 mg/kg, twice weekly and administered alone, and 1.3 mg/kg, once weekly combined with other cytostatic drugs, in 500 ml of infusion fluid, with 25 mg of heparin and 25 mg of hydrocortisone to minimize the frequent risk of local phlebosclerosis.

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