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Study Finds Vaccine Extends Recurrent GBM Survival Rates By 2 To 3 Times

June 3, 2011

Results from Phase 2 study at University Hospitals Case Medical Center, UCSF and Columbia

In data presented at The American Society of Clinical Oncology (ASCO) Annual Meeting, cancer researchers found that the brain tumor vaccine HSPPC-96 for treating recurrent gliobastoma (GBM) has a favorable safety profile and extends survival by two to three times more than the current median survival rate. Patients in the study, conducted at University Hospitals Case Medical Center, University of California, San Francisco and Columbia University, were found to have a median survival of 11 months compared to current three to five month survival.

“The findings are very favorable for patients with this deadly form of brain cancer,” said Andrew Sloan, MD, one of the authors of the study presented at ASCO and Director of the Brain Tumor and Neuro-Oncology Center at University Hospitals Case Medical Center. “The vaccine is one of the few immune therapies designed specifically for patients who are not newly diagnosed, and these encouraging results make this a promising therapy for a more extensive Phase 3 trial.”

HSPPC-96 isolates the heat shock protein, which is part of the immune system. The protein from the patient’s tumor is then reinjected into the skin with an adjuvant, or an agent added to a drug to increase its effect.

The vaccine was developed by Andrew Parsa, MD, PhD, principal investigator of the Brain Tumor Research Center at the University of California, San Francisco. He is collaborating with the Lexington, Massachusetts biotech company called Agenus. Columbia University also is part of the ongoing Phase 2 study designed to evaluate overall survival and immunologic response with HSPPC-96 in patients with first or subsequent recurrence of GBM.

All patients underwent surgery prior to vaccine therapy. However, since the vaccine is made from the patient’s own tumor, the surgery had to be performed at one of the participating sites. The vaccine therapy begins within 5 weeks after surgery and consists of four weekly injections, followed by bi-weekly injections for up to 52 weeks.

“The vaccine is made from a patient’s own cells, so it takes into account what is unique about the patient’s particular tumor””it’s the ultimate in ‘personalized medicine’,” said Dr. Sloan who also is the Peter D. Cristal Chair in Neurosurgery and an Associate Professor of Neurological Surgery at Case Western Reserve University School of Medicine.

In addition to this promising research, UH Case Medical Center’s Seidman Cancer Center physician scientists presented a variety of oral and poster presentations at ASCO. Notably, Cynthia Owusu, MD, breast oncologist, is presenting two important abstracts related to the treatment of older women with breast cancer. Importantly, the first study concludes that one in four women, after 6 months, and one in three, after 12 months, display plummeting physical function which shows a clear need to remedy treatment options to help preserve activity of breast cancer patients later in life. UH Case Medical Center abstracts are highlighted below:

Title: Autologous heat shock protein vaccine (HSPPC-96) for patients with recurrent glioblastoma (GBM): Results of a phase II multicenter clinical trial with immunological assessments.

Monday June 6, 8:00 AM to 12:00 PM

Abstract (http://abstract.asco.org/AbstView_102_85010.html) Background: HSPPC-96 is derived from a patient’s individual tumor and contains glycoprotein-96 (gp96) polypeptide associated with cancer-specific antigenic peptides. Methods: This ongoing single-arm multicenter Phase 2 trial is designed to evaluate overall survival (primary objective) and immunologic response (secondary objective) with HSPPC-96 in patients with first or subsequent recurrence of GBM. Prior treatment with radiotherapy and temozolomide was required. All patients underwent a >90% resection of the recurrence. Vaccine therapy was to be initiated within 5 weeks post-surgery and consisted of 25 µg HSPPC-96, given ID weekly x 4, followed by bi-weekly injections for up to 52 weeks. Results: A total of 33 patients at first recurrence (M:F = 25:8) with a median KPS of 80 were entered. A median of 6 injections (range: 1-15) were administered to the ITT population, with a requisite of 4 vaccinations for the evaluable population. The vaccine was well tolerated with no attributed serious adverse events and no related grade 3 or 4 toxicities. Injection site reaction was seen in 12 patients and fatigue was reported in 9 patients. As of Jan. 2011, the median survival (KM estimates) is 324 days for ITT population (37-877) and 333 days for evaluable population (99-877). 11 patients are still alive and being followed, including 4 beyond one year (374d, 419d, 578d, and 877 days, respectively). All patients with immunological endpoints tested to date exhibited a signiïÂcant innate immune response and all patients demonstrated CD8 T cell IFN gamma production upon restimulation with autologous gp-96; following vaccine administration. Conclusions: HSPPC-96 evokes a speciïÂc and innate immune response in patients with recurrent glioma and survival data available to date indicates HSPPC-96 vaccine provides a possible clinical beneïÂt with a favorable safety proïÂle. Collectively these results provide the impetus for Phase 3 testing against currently approved therapies for patients with recurrent glioblastoma.

Cynthia Owusu, MD, MS
Title: The trajectory of physical functioning during breast cancer treatment of older women.

Saturday June 4, 2:00 PM to 6:00 PM

Abstract (http://abstract.asco.org/AbstView_102_81152.html): Background: We sought to characterize the trajectory of physical functioning during the first 12 months following initial breast cancer diagnosis in older women with stage I-III breast cancer. Methods: Between April 2008 and March 2010 a cohort of women â“°¥65 years with incident stage I-III breast cancer, were enrolled into a prospective cohort study following primary surgery or prior to neoadjuvant chemotherapy. Participants completed a comprehensive geriatric assessment at study entry, six and 12 months. The primary end-points was mean change in the total Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL) scores from baseline to six and 12 months, respectively. A decrease in ADL/IADL scores denoted functional decline. Results: Of sixty-one women enrolled, 48 completed baseline and 12th month CGA, four withdrew from the study, five were lost to follow-up and four have pending 12th month assessment as of 12/31/2010. This report includes the 48 evaluable women. The median age was 73 years, (inter-quartile range 68.5-80 years), 90% had stage I-II disease, 35% had node positive disease, 85% had hormone-receptor positive disease and 35% received adjuvant chemotherapy and/or trastuzumab. The mean change in ADL/IADL scores at six and 12 months was -0.58 [(sd=1.39), p= 0.008] and -0.85 [(sd=2.37), p= 0.02], respectively. The proportion of women who had a decrease, an increase or no change in ADL/IADL scores at six and 12 months from baseline were 24%, 5% and 71%, and 29%, 10% and 61%, respectively. Women with lower than high school education (46% vs. 14%, p=0.03), Karnofsky Performance Status scores ⓰¤80% (67% vs. 17%, p=0.002), any IADL dependency (63% vs. 13%, p=0.0003), Timed-Up-and-Go Test time >14 seconds, (67% vs. 22%, p=0.05) and tumor size â“°¥ 2cm, (50% vs. 13%, p=0.01) at baseline were more likely to develop functional decline at 12 months. Conclusions: One out of every four older woman with breast cancer developed functional decline within six months of treatment increasing to almost one out of every three older woman by 12 months. Studies to identify biologic, molecular and clinical determinants of functional decline in older women with breast cancer in the adjuvant setting are warranted to inform remediation.

Title: Safety and efficacy of single-agent adjuvant trastzumab in older women with breast cancer.

Monday June 6, 8:00 AM to 12:00 PM

Abstract (http://abstract.asco.org/AbstView_102_82820.html): Background: Trastuzumab is a humanized monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) protein. The addition of trastuzumab to adjuvant chemotherapy, either concomitant or sequential, leads to better outcomes for women with HER2-positive breast cancer and in the setting of metastatic disease, single agent trastuzumab is effective and extremely well tolerated. The main adverse effect of trastuzumab is cardiotoxicity, which necessitated discontinuation prior to the planned one year of therapy in 17% of women on adjuvant trials. Since age is a risk factor for the cardiotoxicity of trastuzumab, and women â“°¥ 65 years were under-represented in trastuzumab clinical trials, determination of the safety and efficacy of trastuzumab in this patient population is lacking. This study is designed to define the risk-benefit profile of adjuvant single-agent trastuzumab in older women. Methods: This open label, single arm, multi-center, phase II study will include 124 women with stage I-III, HER2+ (defined as either 3+ by immunohistochemistry or gene amplified by fluorescent in situ hybridization), breast cancer who undergo primary surgery (mastectomy or lumpectomy) with at least a sentinel lymph node dissection, and are unwilling to undergo or are unable to tolerate adjuvant chemotherapy. Trastuzumab will be given, at 8mg/kg IV loading dose followed by 6mg/kg IV every three weeks, for 52 weeks. Patients will be followed prospectively for five years or until death, whichever comes first. The primary objective of the study is to evaluate the three-year cumulative incidence of cardiac events. Secondary objectives include i) the three-year cumulative incidence of asymptomatic decline in Left Ventricular Ejection Fraction; ii) the five-year cumulative incidence of cardiac events; iii) three-year disease-free and overall survival; iv) identification of correlative biomarkers of cardiac events (troponin-I, N-terminal brain natriuretic protein, and pro-inflammatory cytokines); and v) the longitudinal changes in Health-related Quality of Life, functional, cognitive, and mental status. Ten patients have been enrolled thus far.

Note, Dr. Owusu was not a lead author but a participant in the following research:

    * Title: Polypharmacy, potentially inappropriate medications, and chemotherapy-related adverse events among older adults with cancer. http://abstract.asco.org/AbstView_102_84637.html
    * Title: Primary dose reduction (PDR) of chemotherapy (chemo) in patients (Pts) older than age 65 with advanced cancer (Ca) and toxicity outcomes. http://abstract.asco.org/AbstView_102_74120.html
    * Title: Predictors of primary dose reduction (PDR) among patients (pts) age 65 and older receiving adjuvant chemotherapy (chemo). http://abstract.asco.org/AbstView_102_79650.html

Jennifer Eads (Hem/Onc fellow) and Neal Meropol, MD, Chief of Hematology and Oncology
Title: Identification of barriers to clinical trials: The impact of education level.

Monday, June 6, 9:30 AM to 12:30 PM

Abstract (http://abstract.asco.org/AbstView_102_76932.html): Background: Patient (pt) participation in clinical trials remains low. We previously described psychosocial and practical barriers to enrollment (J NCCN, 2007). During development of an intervention to improve pt preparation for consideration of clinical trials, we conducted a survey to identify pt characteristics associated with knowledge and attitudinal barriers (NIH R01 CA127655). Methods: Eligible pts were adults with a cancer diagnosis scheduled for their first medical oncologist visit. Informed consent was obtained to participate in a survey before the initial consultation. The survey included demographic information and an assessment of potential clinical trials barriers. Items included 19 correct-incorrect knowledge questions and 29 attitudinal barriers that were assessed on a 5-point Likert scale (1=strongly disagree, 5=strongly agree; 4-5 scored as “positive”). Cronbach’s alphas and factor analysis were used to develop four attitudinal barriers subscales: fears and emotions, knowledge and finances, logistics, and mistrust of the medical system. Multiple linear regression analysis examined the relationship of demographics with barriers. Results: 156 pts enrolled: 40% female, 23% African American (AA), 42% college educated, mean age 58.7 years. Non-AA pts answered more knowledge questions correctly (mean 11.5 vs. 9.1, p=0.002) as did college educated pts (mean 13 vs. 9.5, p<0.001). Race was not associated with attitudinal barriers in the multivariable analysis. College education was associated with fewer attitudinal barriers (fears and emotions, p=0.092; knowledge and finances, p=0.005; logistics, p<0.001; mistrust of the medical system, p=0.049). Females scored higher on the fears and emotions subscale (p=0.015). Most commonly cited attitudinal barriers were fear of side effects on a clinical trial (54% of pts), not knowing where to find a clinical trial (40%) and unwillingness to travel extra distance for a clinical trial (39%). Conclusions: Lower educational level and female gender, but not race, are independently associated with barriers to clinical trials, suggesting a tailored approach to addressing these barriers is warranted. Socioeconomic status rather than race should be a focus of these efforts.

Erica L. Campagnaro, MD
Title: Survival outcomes in elderly patients with plasma cell myeloma: The three-decade Eastern Cooperative Oncology Group (ECOG) experience.

Saturday June 4, 8:00 AM to 12:00 PM

Abstract (http://abstract.asco.org/AbstView_102_82373.html) : Background: Successful treatment of plasma cell myeloma (PCM) includes cytotoxic chemotherapy, high-dose chemotherapy with autologous stem cell transplant (ASCT), immunomodulatory drugs and proteasome inhibitors. Landmark papers by Kumar et al and Brenner et al in 2008, and Turesson et al in 2010, showed significant gains in median overall survival (OS) of PCM patients but these gains were attributed primarily to age < 65 years. Marginal improvement seen in older patients did not reach significance. We examined outcome for patients treated on frontline ECOG protocols over the past 33 yrs to assess whether there has been survival improvement in elderly patients. Methods: We reviewed 4 phase III study data for previously untreated PCM patients. ASCT regimens were excluded. OS was analyzed using Kaplan-Meier and group differences were tested using 2-tailed log-rank test. Cohorts were identified based on date of accrual to clinical trial: A 1988-1993, B 1994-2000, and C 2001-2006. Results: 1,528 patients were treated (Table). 727 (48%) were > 65 yr. 358 pts (23%) were age 70-79 yr and 48 pts (3%) were > 80 yr. For all pts, 5 yr probability of OS was significantly better in cohort C (51%) as compared to cohorts A (31%) and B (29%), respectively (p<0.0001). For pts > 65 yr, this effect on OS still was seen but substantially diminished (39% on C versus 26% on A and B, p=0.012), while in the younger cohort effect is more pronounced (63% on C, 35% on A and 32% on B). Conclusions: OS in elderly PCM pts has improved but OS gains still lag behind younger PCM pts. Increased comorbidity, treatment-related toxicity, physician/patient biases, and differences in disease biology in elderly patients are all possible contributing factors to worse outcomes. In-depth review of these variables may contribute to improved design of future clinical trials for elderly PCM pts.

Henry B. Koon, MD
Title: Phase II AIDS Malignancy Consortium trial of imatinib in AIDS-associated Kaposi’s sarcoma.

Saturday June 4, 8:00 AM to 12:00 PM

Abstract (http://abstract.asco.org/AbstView_102_85031.html) : Background: KS is a disease of multi-focal vascular proliferation that requires infection with KS herpes virus (KSHV/HHV-8). KSHV infected cells demonstate activation of the c-kit and platelet derived growth factor (PDGF) receptors. Partial KS regression in 5/10 patients was observed in a pilot study using the c-kit/PDGF-R inhibitor imatinib (Novartis Pharmaceuticals) suggesting this agent has activity in KS. Methods: The primary objective was to estimate the response rate in AIDS-related KS. Secondary objectives included investigation biomarkers of response and imatinib pharmacokinetics in patients on cART. Plasma concentrations of CCL5, IFNg, IL-6 and FGF-b were measured. Patients were treated with imatinib 400mg/day orally for up to 12 months with the option to dose escalate to 600mg/day at 3 months if disease was stable. Results: Thirty patients were treated at 12 AMC sites. Median CD4 count was 263 (19-819). 79% had undetectable HIV RNA. Ten (33.3%) showed partial response, 6 (20%) had stable disease and 7 (23.3%) showed KS progression. Nine patients completed 52 weeks of imatinib and the median treatment duration was 22.5 weeks (0.3-52.7). Only 5 patients (16.7%) discontinued therapy due to adverse events including grade 3 hypophosphatemia (2) allergic reaction (1), cellulitis (1), depression (1) and grade 4 elevation of CK (1). Pharmacokinetic analysis of the AUC ratios demonstrated that actual imatinib AUC levels were significantly higher than predicted (P=0.036), but there was no difference between actual and predicted AUC for the active metabolite (P=0.441), suggesting the anti-retroviral regimens influenced imatinib metabolism. Levels of CCL5, IFNg, IL-6 and FGF-b correlated with response in a pilot study; however, none of these growth factors predicted response in this larger study. Conclusions: Imatinib has activity in AIDS-related Kaposi’s sarcoma. The potential interactions with antiretroviral drugs did not correlate with increased toxicity. Thirty percent of patients showed long-term clinical benefit and remained on imatinib for the entire year. These results suggest this regimen is well tolerated and may be an alternative to cytotoxic chemotherapy for some patients with AIDS-related KS.

Charles Kunos, MD, PhD
Title: Phase II trial of pelvic radiation, weekly cisplatin, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) for locally advanced cervical and vaginal cancer.

Friday June 3, 2:00 PM to 6:00 PM

Abstract (http://abstract.asco.org/AbstView_102_74945.html) : Background: This on-going clinical trial assesses the safety and clinical activity of 3x weekly intravenous 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) co-administered with 1x weekly intravenous cisplatin and daily pelvic radiation in patients with locally advanced cervical and vaginal cancer. 3-AP potently inhibits ribonucleotide reductase and clinically is being evaluated as a chemoradiation sensitizer. Here, we report the preliminary toxicity and response data. Methods: Patients with stage IB2 to IVB cervical cancer (n = 12) or stage II to IV vaginal cancer (n = 2) underwent 2-hour 3-AP infusions (25 mg/m2) 3x weekly during 5 weeks of cisplatin (40 mg/m2, 70 mg maximum) chemoradiation. Brachytherapy followed. Toxicity was monitored by common terminology criteria for adverse events v3.0. Response was assessed by exam and 3-month posttherapy positron emission tomography (PET/CT). Institutional review board approval was provided for conduct of research. Results: 14 patients tolerated 206 (98%) of 210 planned 3-AP infusions. Four patients experienced reversible 3-AP-related grade 3 leukopenia or thrombocytopenia. Two patients had reversible, possibly 3-AP-related, grade 3 hypokalemia and hyponatremia. One patient with pre-existing portal hypertension had a less than 30-day post-chemoradiation grade 4 hemorrhage secondary to an iatrogenic Mallory-Weiss tear of gastric varices, occurring before brachytherapy and resulting in death. 13 (93%) of 14 patients achieved durable complete clinical responses (median follow-up 9 months, range 3-18 months). 10 (91%) of 11 patients had 3-month PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. Conclusions: 3-AP given 3x weekly co-administered with cisplatin chemoradiation is well tolerated and associated with a high clinical and metabolic response. Further accrual is on-going (Grant: Case Western Reserve University 5U01 CA062502).

Sanford D. Markowitz, MD, PhD

Dr. Markowitz will be part of a virtual meeting (http://www.asco.org/ASCOv2/MultiMedia/Virtual+Meeting?&vmview=vm_session_presentations_view&confID=102&sessionID=3973) discussing the topic of “Biomarkers for the Early Detection of Colon Cancer,” amongst other speakers within the larger topic of, “An Update on Biomarkers for the Early Detection of Cancer, Prediction of Prognosis, and as Surrogate Endpoints for Cancer Prevention Trials”

Neal J. Meropol, MD ““ Note, Dr. Meropol was not a lead author but participated in the following research:
Title: Efficacy endpoints of RTOG 0247: A randomized phase II study of neoadjuvant capecitabine (C) and irinotecan (I) or C and oxaliplatin (O) with concurrent radiation therapy (RT) for locally advanced rectal cancer. http://abstract.asco.org/AbstView_102_79385.html
Title: Utilization and costs of non-evidence-based (non-EBM) antineoplastic agents in patients with metastatic colon cancer (mCC). http://abstract.asco.org/AbstView_102_78955.html
Title: Circulating protein and cellular biomarkers of sunitinib in patients with advanced neuroendocrine tumors. http://abstract.asco.org/AbstView_102_80750.html
Title: A phase I study of capecitabine in combination with yttrium-90 labeled resin microspheres (SIR-Spheres) in patients (pts) with advanced cancer. http://abstract.asco.org/AbstView_102_83792.html

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