Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

G. Otterson



Author of

  • +

    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      P1.11-026 - Final Results of a Phase 2 Trial of the Oncolytic Virus Reovirus Serotype 3-Dearing Strain (REOLYSIN®) in Metastatic NSCLC Patients with a Ras-activated Pathway. (ID 1994)

      09:30 - 09:30  |  Author(s): G. Otterson

      • Abstract

      Background
      Reovirus is a naturally occurring virus which preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. In preclinical studies, reovirus induces cell cycle arrest, acting synergistically with standard cytotoxic agents. We have hypothesized that patients with EGFR-mutated, EGFR-amplified, BRAF or Kras-mutated NSCLC should all have a common downstream activated Ras pathway and should be susceptible to treatment with reovirus.

      Methods
      We conducted a Fleming, single-arm, phase II study to evaluate safety and the objective response rate (primary end-points), as well as 6-month progression-free and 1 year survival (secondary end-points) of metastatic NSCLC patients treated with reovirus in combination with paclitaxel/carboplatin (P/C). Eligible patients had ECOG PS 0-2, adequate organ function, no prior chemotherapy for metastatic disease, and tumors with the specified above genotype, as per CLIA certified laboratory testing. Prior adjuvant chemotherapy, or erlotinib/gefitinib for pts with EGFR-mutant tumors was permitted. Patients received Reovirus (3 x 10[10 ]TCID~50~) intravenously daily on days 1-5, in combination with P/C at initial doses of P 200 mg/m[2] and C AUC 6, on day 1 of each 21-day cycle. Due to exacerbation of prior colitis and febrile neutropenia (1 each) in the first two pts, doses were subsequently reduced to P 175 mg/m m[2] and C AUC 5.

      Results
      Overall, 37 patients received 209 cycles (per pt median 4, range 1 to 18). Grade 3-4 toxicity included febrile neutropenia (3 pts), G3 diarrhea (2 pts), G3 anemia (8 pts), fatigue in 6 pts (5 G3, 1 G4), nausea/vomiting and thrombocytopenia (2 pts each), electrolyte abnormalities, and single G3 episodes of arthralgia and transaminitis. Molecular tumor demographics included: 20 Kras (2 G12A, 9 G12C, 1 G12D, 1 G12R, 1 G12S, 3 G12V, 1 G13C, 1 G13R, 1 G12C/V double mutant), 3 EGFR exon 19, 4 BRAF V600E mutations, and 10 EGFR amplified only. Response evaluation showed 11 RECIST partial responses (30%) (EGFR amp 5, BRAF 2, Kras 3, EGFR mut 1), 21 SD, and 4 PD. PFS (by CT and PET) at 6 months for 36 patients with enough follow up to date is 36%, with PET results influencing switching to second line therapy in several patients with SD by CT. Sixteen patients received 6 or more cycles. One year survival was 53%.

      Conclusion
      Reovirus can be administered safely in combination with P/C and patient selection by Ras-activated pathway is feasible in the clinical setting. Overall clinical efficacy is encouraging. Randomized evaluation is planned.

  • +

    P2.01 - Poster Session 2 - Cancer Biology (ID 145)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
    • +

      P2.01-004 - Type of P53 mutation influences oncogenic potential and spectrum of associated K-ras mutations in lung specific transgenic mice. (ID 1972)

      09:30 - 09:30  |  Author(s): G. Otterson

      • Abstract

      Background
      p53 mutations have been categorized as type I (contact) and type II (conformational) mutations. Differential effects of type I vs. type II p53 mutations in spontaneous lung tumor formation, and their relationship with secondary genetic alterations have not been previously reported. .

      Methods
      We evaluated the potential of two common type I (273H) and type II (175H) mutations under the transcriptional control of the human surfactant protein C (SP-C) promoter to induce lung tumors in transgenic mice. Necropsies of 138 non-transgenic, 207 SP-C-p53-273H and 171 SPC-p53-175H transgenic mice in progressive age cohorts were performed.

      Results
      Ninety-one tumors, all adenocarcinomas, were observed; 8 (5.8%), 37 (17.9%) and 46 (26.9%) in non-transgenics, p53-273H and p53-175H, respectively (non-transgenic vs. 273H, p=0.010; non-transgenic vs. 175H, p= 0.0003; logistic regression). Type II p53 mutants had an earlier onset of tumors; 23 of 98 p53-175H mice developed tumors before the age of 13 months, compared to 7 of 108 p53-273H mice (p=0.012, logistic regression). K-ras mutations occurred in a substantial proportion (21 of 50, 42%) of murine lung tumors sequenced. For both the non-transgenic and the p53-273H transgenics, tumor K-ras codon 12-13 mutations occurred after 13 months with a peak incidence at 16–18 months. However, for the p53-175H transgenics K-ras codon 12-13 mutations were observed as early as six months, with a peak incidence between the ages of 10-12 months. Codons 12-13 were the predominant location in p53-175H transgenics (6 of 7), whereas codon 61 (6 of 10) was more common in p53-273H transgenics.

      Conclusion
      The observation of accelerated tumor onset, early appearance and high frequency of K-ras codon 12-13 mutations in type II p53-175H mice confirms the enhanced oncogenic function of conformational p53 mutations, and the gains in early genetic instability for tumors containing these mutations compared to contact mutations. These data would suggest that not only the presence, but also the type of p53 mutations in human lung cancer should be considered when evaluating prognosis and developing treatment strategies for this malignancy. These mice develop a single-lung tumor that is easy to follow with CT imaging. Thus, these animal models provide a framework for evaluation of the effects of these mutations on response to standard and novel anticancer treatment interventions.

  • +

    P2.13 - Poster Session 2 - SCLC (ID 201)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      P2.13-002 - Randomized Phase II Study of Single Agent OSI-906, an Oral, Small Molecule, Tyrosine Kinase Inhibitor (TKI) of the Insulin Growth Factor-1 Receptor (IGF-1R) Versus Topotecan for the Treatment of Patients with Relapsed Small Cell Lung Cancer (SCLC) (ID 920)

      09:30 - 09:30  |  Author(s): G. Otterson

      • Abstract

      Background
      SCLC typically presents with advanced (extensive stage) disease. Despite an initial response to chemotherapy, they all relapse and rarely survive beyond 2 years. Treatment of relapsed SCLC is limited (topotecan) and dependent on the response to initial chemotherapy (sensitive vs. refractory relapse). Downstream activation of PI3K-AKT, through IGF-1R pathway signaling plays a role in both, growth/survival and resistance to chemotherapy in SCLC. Growth inhibition and chemosensitization with IGF-1R inhibitors correlates with the PI3K-AKT inhibitory signaling and suggests AKT activation as a potential biomarker. OSI-906, is a well tolerated oral, small molecule, potent inhibitor of IGF-1R

      Methods
      A phase II randomized study comparing the efficacy of OSI-906 vs topotecan in patients with rSCLC is currently being conducted. Primary endpoint is PFS, summarized with the K-M method. An increase in median PFS from 2.5 to 4.175 months (in the experimental arm B) is proposed. A total of 95 patients are planned. Biomarkers of IGF-1R inhibition are explored in plasma, PBMC and using Radiomics. Eligible patients must have proven rSCLC, platinum sensitive (sen) or resistant (res) disease, ECOG PS 0-2 and adequate hematologic, renal and hepatic function. Fasting glucose <160 mg/dl, QTc < 450 msec and measurable disease by RECIST v1.1 are required. Pregnant, breast-feeding, diabetic and cirrhotic patients as well as those taking insulin/insulinotropic agents are excluded. Patients are randomized (2:1) to the experimental arm (B): OSI-906, 150 mg PO BID, until progression or to the standard arm (A): topotecan, 1.5 mg/m[2] IV daily x5 OR 2.3 mg/m[2] PO daily x5, for 4 cycles. Crossover to OSI-906 is allowed.

      Results
      Figure 1 Thirty-three patients have been enrolled; A=10 (res=6, PS 2=2) and B=23 (res=15, PS 2=4). M/F= 13/20; ECOG PS 0/1/2 = 8/19/6. Platinum sen/res = 12/21. Two patients were not treated (A/B = 1/1). Adverse events are described in Table 1. No responses have been observed. Only 2/6 and 1/15 patients in arms A and B respectively achieved SD at 6 weeks. Median PFS (A/B) was 2.1 (95% CI; 0.6, 3.6) and 1.3 (95% CI; 1.0, 1.4) months respectively (p = 0.0149). OS was not reached in arm A and 2.7 (95% CI; 1.5, …) months in arm B (p = 0.1716).

      Conclusion
      OSI-906 is safe in rSCLC patients. In our unselected, high risk population, efficacy in both arms, but particularly in arm B appears suboptimal. The study continues to accrue to reach the sample size and follow up time needed for more robust conclusions.