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J. Nemunaitis
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ORAL 11 - Clinical Trials 1 (ID 100)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:A.K. Nowak, F. Detterbeck
- Coordinates: 9/07/2015, 10:45 - 12:15, 702+704+706
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ORAL11.02 - Phase I Study of Anti-Mesothelin Antibody Drug Conjugate Anetumab Ravtansine (ID 1574)
10:45 - 12:15 | Author(s): J. Nemunaitis
- Abstract
- Presentation
Background:
Anetumab ravtansine (BAY 94-9343) is a novel fully humanized anti-mesothelin IgG1 antibody conjugated to a ravtansine, a maytansine derivative DM4 antitubulin cytotoxic agent. We report results from a phase I study evaluating the safety, PK and tumor response in patients (pts) with advanced solid tumors treated with anetumab, with a particular focus on patients with mesothelioma.
Methods:
Anetumab was given IV every 21 days (q3w) in 77 pts: 45 pts in 10 dose escalation cohorts from 0.15 to 7.5 mg/kg (21 mesothelioma, 9 pancreatic, 5 breast, 4 ovarian, 6 other), and 32 pts in 2 expansion cohorts (12 mesothelioma and 20 ovarian); 38 pts were treated at MTD in escalation and expansion cohorts (16 mesothelioma, 21 ovarian, 1 breast). Clinical and laboratory safety assessments were made on D1, D8 and D15 in C1-C3 and on D1 in subsequent cycles. Tumor assessments were made q6wks up to C8 and q12wks thereafter. Mesothelin expression in archival tumor samples was assessed retrospecively by IHC (SP74, Ventana).
Results:
Thirty-two males and 45 females were treated [mean age 62 yrs (range, 18-84 yrs), body weight 77 kg (44-113 kg), ECOG ≤1, median prior cytotoxic regimens: overall 4 (1-9), mesothelioma 1 (1-4)]. Non-tolerated anetumab dose was 7.5 mg/kg (DLTs: 1 pt with G2 keratitis and G3 neuropathy, 1 pt with G4 keratitis and G2 neuropathy). Anetumab MTD was 6.5 mg/kg (DLT: G3 AST increase). Only one DLT occurred at doses below MTD (G3 hyponatremia, 5.5 mg/kg). No drug-related deaths and few drug-related SAEs (7 total and 5 at MTD) were reported. Seventeen of 38 (45%) pts total or 7 of 16 (44%) mesothelioma pts at MTD had drug-related AE requiring dose reduction (G1-4 keratitis, G2-3 neuropathy, G3 fatigue, anorexia, asthenia, diarrhea, N&V, AST increase). LFT increases were the most common drug-related laboratory abnormality at MTD: AST in 7 pts (2 G3), ALT in 6 pts (no G3), alkaline phosphatase in 4 pts (one G3) and bilirubin increase in 1 pt (no G3). There were no drug-related G3 hematological abnormalities at any dose. Fourteen of 38 (37%) pts total or 4 of 16 (25%) mesothelioma pts at MTD had G1-4 keratitis (worst G3-4 in 3 pts, blurred vision in 10, dose reduction in 8, dose delay in 11, all fully reversible). Anetumab at the MTD showed a PR in 6 pts (19%) and SD in 18 pts (47%) overall. Five of 16 (31%) mesothelioma pts at the MTD had durable PR (>600 days in 4 pts) and 7 (44%) had SD. Five PRs occurred in 11 mesothelioma pts who received anetumab as second line treatment (45% response rate).
Conclusion:
Anetumab at the MTD (6.5 mg/kg) showed encouraging efficacy with durable PR in pts with advanced mesothelioma. At the MTD, all drug-related AEs were reversible and non-life-threatening but required dose reduction in about half of pts, most commonly due to G1-4 keratitis and G2-3 peripheral neuropathy. Given this benefit-risk ratio, the recommended phase II dose of anetumab in second line treatment of advanced mesothelioma is 6.5 mg/kg IV q3w.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-003 - T-Cytotoxic Specific Immunotherapy in NSCLC with Brain Metastases NCT00104780 (ID 1202)
09:30 - 17:00 | Author(s): J. Nemunaitis
- Abstract
Background:
Brain metastases (BM) come with poor prognosis (median survival 3 to 6 months) and data are lacking as patients are often excluded from clinical trials.
Methods:
We present the results of a subgroup of NSCLC patients with BM treated with OSE-2101 (T-cytotoxic specific immunotherapy combining 9 epitopes targeting 5 tumor associated antigens and 1 pan-DR epitope) during a phase IIb study of OSE-2101 (1 injection per 3 week for 6 injections followed by 1 injection every 2 to 3 months) in advanced stage IIIB and IV NSCLC (Barve et al. 2008. J Clin Oncol 26:4418-4425). Patients were eligible whatever the number of prior chemotherapy (chemo) lines (65.5% entering 3rd line) and patients with stable BM for 2 months could be included. Six out of 64 treated patients had BM prior to inclusion and are reviewed.
Results:Table 1: NSCLC patients included with BM
AA: African-American, CAU: Caucasian, Chemo: chemotherapy, F: female, Gy: Gray, M: male, RT: radiotherapy, WBRT: whole brain radiotherapyPatient 108 150 169 132 133 135 Gender F M M M M M Ethnic origin CAU CAU CAU CAU AA CAU Age (years) 46 61 58 79 46 57 ECOG performance status 1 1 1 1 1 1 Previous treatment RT 30 Gy Chemo 2 lines WBRT 30 Gy Chemo 2 lines RT 30 Gy Chemo 2 lines WBRT 30 Gy Chemo 3 lines RT 30 Gy Chemo 1 line WBRT 30 Gy Chemo 3 lines Table 2: Response to therapy
* Patient still alive at the time of the last follow up, ** treatment stopped after 2 injections for progressive disease. CTL: cytotoxic T lymphocytes, HTL: helper T lymphocytes, mo: months, OS: Overall survival, The 6 BM patients present long survival (median 13 mo, range 7-41) considering the advanced stage and the poor prognosis of these heavily pretreated patients. All patients had received from 1 to 3 previous chemo lines. Evaluation of CTL responses to 5 epitopes of OSE-2101 in 5 patients shows that each patient had a CTL response to at least one and up to 5 epitopes. Surprisingly patients with positive HTL response (patient 108, 150, 169) achieve the longest OS when compared with negative HTL patients (132 and 133).Patient 108 150 169 132 133 135 OS 30.16 mo 41 mo* 16.5 mo 9.6 mo 11 mo 7 mo** Time without progression 11.57 mo 24.39 mo 11.9 mo 4.53 mo 6.2 mo 2 mo*[2] CTL response (positive epitopes out of 5 tested) 3 2 5 2 1 Not tested HTL response + + + - - Not tested
Conclusion:
Long OS has been documented in NSCLC patients with BM treated with T-specific immunotherapy following RT and 1 to 3 previous chemo lines.
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P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.08-011 - Avelumab (MSB0010718C), an Anti-PD-L1 Antibody, Evaluated in a Phase Ib Trial in Patients with Advanced Mesothelioma (ID 790)
09:30 - 17:00 | Author(s): J. Nemunaitis
- Abstract
Background:
The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. The phase Ib study (NCT01772004) is an open-label, parallel group expansion trial in patients with metastatic or locally advanced solid tumors that includes a cohort of patients with advanced, unresectable mesothelioma.
Methods:
This trial cohort is enrolling patients with histologically or cytologically confirmed unresectable mesothelioma (pleural or peritoneal) that has progressed after treatment with either a platinum-pemetrexed–containing regimen or a platinum-based regimen followed by pemetrexed (or vice versa). Eligible patients must have available tumor archival material or fresh biopsy, and an ECOG performance status of 0 or 1 at trial entry, and disease with at least 1 measurable lesion that has not been irradiated. Exclusion criteria include prior therapy with immune checkpoint drugs, a known history of autoimmune disease, or recent anticancer treatment (within the 28 days prior to study start). Up to 50 eligible patients will receive avelumab at 10 mg/kg as an infusion Q2W. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Treatment may be continued despite progression according to RECIST 1.1 if the patient’s clinical status is stable and, according to investigator opinion, there is no need to start salvage therapy. The primary objective of the trial is to assess the safety and tolerability of avelumab. Select secondary objectives include: assessment of best overall response (BOR) and progression-free survival (PFS) according to RECIST 1.1; assessment of immune-related BOR and immune-related PFS (using the modified Immune-Related Response Criteria); and assessment of overall survival. Association between tumor PD-L1 expression and efficacy will be evaluated. Changes in soluble factors and immune cell profiling will be characterized and immunomonitoring will occur at each visit. Tumor assessments will be performed every 6 weeks until progression. Tumor tissue from the most recent biopsy or surgical specimen will be collected prior to the initiation of trial treatment, and fresh biopsies may be optionally collected on day 43 and at the end-of-treatment visit. At each visit during the treatment phase, adverse events will be assessed and graded according to NCI-CTCAE v4.0. Enrollment in this study began in September 2014. *Proposed INN.
Results:
not applicable
Conclusion:
not applicable
