Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I.

INTRODUCTION: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). METHODS: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. RESULTS: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. DISCUSSION: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018.

SMA valiant trial: a prospective, double-blind, placebo-controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy.

INTRODUCTION: An open-label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12-month, double-blind, cross-over study of VPA in ambulatory SMA adults. METHODS: There were 33 subjects, aged 20­55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10­20 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes. RESULTS: Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months. CONCLUSIONS: VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults.

A biologic-device combination product delivering tumor-derived antigens elicits immunogenic cell death-associated immune responses against glioblastoma.

BACKGROUND: IGV-001 is a personalized, autologous cancer cell-based immunotherapy conceived to deliver a tumor-derived antigenic payload in the context of immunostimulatory signals to patients with glioblastoma (GBM). IGV-001 consists of patient-derived GBM cells treated with an antisense oligodeoxynucleotide against insulin-like growth factor 1 receptor (IGF1R) and placed in proprietary biodiffusion chambers (BDCs). The BDCs are then exposed to 5-6 Gy radiation and implanted at abdominal sites for ~48 hours. IGV-001 has previously been shown to be generally safe with promising clinical activity in newly diagnosed GBM patients. METHODS: Mouse (m) or human (h) variants of IGV-001 were prepared using GL261 mouse GBM cells or human GBM cells, respectively. BDCs containing vehicle or mIGV-001 were implanted in the flanks of C57BL/6 albino female mice in preventative and therapeutic experiments, optionally in combination with a programmed cell death 1 (PD-1) blocker. Bioactivity of the general approach was also measured against hepatocellular carcinoma Hepa 1-6 cells. Mice were followed for the growth of subsequently implanted or pre-existing tumors and survival. Draining lymph nodes from mice receiving mIGV-001 were immunophenotyped. mIGV-001 and hIGV-001 were analyzed for extracellular ATP and high mobility group box 1 (HMGB1) as indicators of immunogenic cell death (ICD), along with flow cytometric analysis of viability, surface calreticulin, and reactive oxygen species. Stress and cell death-related pathways were analyzed by immunoblotting. RESULTS: IGV-001 causes oxidative and endoplasmic reticulum stress in GL261 cells, resulting in a cytotoxic response that enables the release of antigenic material and immunostimulatory, ICD-associated molecules including ATP and HMGB1 from BDCs. Immunophenotyping confirmed that IGV-001 increases the percentage of dendritic cells, as well as effector, and effector memory T cells in BDC-draining lymph nodes. Consistent with these observations, preventative IGV-001 limited tumor progression and extended overall survival in mice intracranially challenged with GL261 cells, a benefit that was associated with an increase in tumor-specific T cells with effector features. Similar findings were obtained in the Hepa 1-6 model. Moreover, therapeutically administered IGV-001 combined with PD-1 delayed progression in GBM-bearing mice. CONCLUSIONS: These results support treatment with IGV-001 to induce clinically relevant ICD-driven anticancer immune responses in patients with GBM.

Long-term safety of the tafenoquine antimalarial chemoprophylaxis regimen: A 12-month, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Tafenoquine is a long-acting 8-aminoquinoline approved for antimalarial prophylaxis for ≤6 months. Additional data is needed to establish the drug's longer-term safety profile, including potential ophthalmic or neuropsychiatric effects. METHOD: This was a randomized, double-blind, placebo-controlled trial in 600 healthy adults. Eligible subjects were randomized 1:1 to receive tafenoquine 200 mg weekly (antimalarial prophylactic regimen) or placebo for 52 weeks. Scheduled safety visits occurred at Weeks 4, 12, 24, 52 (dosing completed), and 64 (final follow-up). Safety assessments included ophthalmic changes, general and neuropsychiatric adverse events (AEs), and laboratory value changes. RESULTS: The percentage of subjects with a protocol-defined Serious Ophthalmic Safety Event was lower in the Tafenoquine Group (18.2%) versus the Placebo Group (19%, p = 0.308). There was no significant difference between the percentages of subjects with at least one AE in the Tafenoquine Group (91.0%) versus Placebo (89.9%, p = 0.65). Common AEs seen at a significantly higher incidence for tafenoquine included reversible cornea verticillata (54.5%) and nausea (13.0%), leading to 0.0% and 0.7% discontinuations. Psychiatric AEs occurred at similar percentages in both study groups. Reversible changes in hemoglobin, methemoglobin, creatinine, and blood urea nitrogen (BUN) were noted. CONCLUSIONS: This study supports the safety of extended 52-week tafenoquine prophylaxis. CLINICAL TRIAL REGISTRATION NUMBER/CLINICALTRIALS. GOV IDENTIFIER: NCT03320174.

Reliability of the Modified Hammersmith Functional Motor Scale in young children with spinal muscular atrophy.

INTRODUCTION: The test-retest reliability of the Modified Hammersmith Functional Motor Scale (MHFMS) in children with spinal muscular atrophy (SMA) ≤30 months of age was assessed. The age at which typically developing children (TD) achieve maximum MHFMS scores was also studied. METHODS: Twenty-two children with SMA type II [mean age (SD) = 20 (5) months, range 9-30 months) were tested twice using the MHFMS. Twenty-five TD children [mean age (SD) = 18 (7) months, range 9-30 months) were tested once. RESULTS: The average difference between MHFMS scores for SMA children was 0.18 [first assessment: mean (SD) = 12.8 (9.8); second assessment: mean (SD) = 13.0 (8.8)]. Reliability was excellent (ICC(1,3) = 0.96, SEM 1.86). TD participants had MHFMS scores ranging from 36 to 40 [mean (SD) = 39.2 (1.2)] and achieved maximum test scores at 12 months of age. DISCUSSION: MHFMS scores in young children with SMA type II showed excellent test-retest stability. This suggests that the MHFMS can be used reliably in this younger population for clinical trials and follow-up.

Phase Ib Clinical Trial of IGV-001 for Patients with Newly Diagnosed Glioblastoma.

PURPOSE: Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma. PATIENTS AND METHODS: This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4-6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies. RESULTS: Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001-treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine-DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted. CONCLUSIONS: IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).

Perspectives on clinical trials in spinal muscular atrophy.

Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy.

Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial.

BACKGROUND: Brain metastases occur in up to 40% of all patients with systemic cancer. We aimed to assess whether stereotactic radiosurgery provided any therapeutic benefit in a randomised multi-institutional trial directed by the Radiation Therapy Oncology Group (RTOG). METHODS: Patients with one to three newly diagnosed brain metastases were randomly allocated either whole brain radiation therapy (WBRT) or WBRT followed by stereotactic radiosurgery boost. Patients were stratified by number of metastases and status of extracranial disease. Primary outcome was survival; secondary outcomes were tumour response and local rates, overall intracranial recurrence rates, cause of death, and performance measurements. FINDINGS: From January, 1996, to June, 2001, we enrolled 333 patients from 55 participating RTOG institutions--167 were assigned WBRT and stereotactic radiosurgery and 164 were allocated WBRT alone. Univariate analysis showed that there was a survival advantage in the WBRT and stereotactic radiosurgery group for patients with a single brain metastasis (median survival time 6.5 vs 4.9 months, p=0.0393). Patients in the stereotactic surgery group were more likely to have a stable or improved Karnofsky Performance Status (KPS) score at 6 months' follow-up than were patients allocated WBRT alone (43% vs 27%, respectively; p=0.03). By multivariate analysis, survival improved in patients with an RPA class 1 (p<0.0001) or a favourable histological status (p=0.0121). INTERPRETATION: WBRT and stereotactic boost treatment improved functional autonomy (KPS) for all patients and survival for patients with a single unresectable brain metastasis. WBRT and stereotactic radiosurgery should, therefore, be standard treatment for patients with a single unresectable brain metastasis and considered for patients with two or three brain metastases.

Patient-Reported Outcomes for Determining Prognostic Groups in Veterans With Advanced Cancer.

CONTEXT: Physicians overestimate survival in patients with advanced cancer. Patient-reported outcomes could provide another way to estimate survival. We previously reported four prognostic groups based on Karnofsky Performance Status, Functional Assessment of Cancer Therapy physical well-being subscale, and Memorial Symptom Assessment Scale-Short Form physical symptom distress subscale scores. OBJECTIVES: To determine the validity of these four prognostic groups. METHODS: We performed prospective surveys. Data from a total of 880 Veterans Affairs Medical Center patients, 417 in the First Cohort and 463 in the Validation Cohort, were analyzed. Both inpatients and outpatients were prospectively recruited in Institutional Review Board-approved studies from August 1999 to September 2009. Survival was measured from the date of entry until death or December 1, 2009. Patients completed self-assessments with the Functional Assessment of Cancer Therapy and Memorial Symptom Assessment Scale-Short Form. Analysis of variance was used to test differences between groups in continuous variables; a generalized Wilcoxon test was used for differences between groups for survival. RESULTS: The average age in the Validation Cohort was 66.5 years and 98% were men. The majority of patients had metastatic cancer (90%), with lung (28%) and prostate (26%) cancers being predominant. The median Karnofsky Performance Status was 70. Median survival was 33, 46.5, 124, and 209.5 days for the four prognostic groups (P < 0.0001, all pair-wise comparisons P < 0.02). CONCLUSION: The four prognostic groups remained distinct in the prospective cohort. Small differences in patient-reported physical well-being can halve survival estimates. Patient-reported outcomes can correct for physician overestimate of prognosis. This study provides a way to use patient-reported outcomes for prognosis in patients with advanced cancer, with important implications for assessment.

Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group.

PURPOSE: To compare the outcome of treatment of mediastinoscopy-verified N2 non-small-cell lung cancer treated with induction chemotherapy followed by either surgery or radiotherapy (RT), with both options followed by consolidation chemotherapy. METHODS AND MATERIALS: A randomized Phase III trial for Stage IIIA (T1-T3N2M0) non-small cell lung cancer was conducted by the Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group between April 1990 and April 1994. After documentation of N2 disease by mediastinoscopy or anterior mediastinotomy, patients received induction chemotherapy with cisplatin, vinblastine, and mitomycin-C. Mitomycin-C was later dropped from the induction regimen. Patients were then randomized to surgery or RT (64 Gy in 7 weeks) followed by cisplatin and vinblastine. RESULTS: RTOG 89-01 accrued 75 patients, of whom 73 were eligible and analyzable. Twelve patients received induction chemotherapy but were not randomized to RT or surgery thereafter. Forty-five patients were randomized to postinduction RT or surgery. Of the analyzable patients, 90% had a Karnofsky performance score of 90-100, 18% had weight loss >5%, 37% had squamous cell histologic features, and 54% had bulky N2 disease. The distribution of bulky N2 disease was uniform among the treatment arms. The incidence of Grade 4 toxicity was 56% in patients receiving mitomycin-C and 29% in those who did not. Only 1 patient in each group had acute nonhematologic toxicity greater than Grade 3 (nausea and vomiting). No acute Grade 4 radiation toxicity developed. The incidences of long-term toxicity were equivalent across the arms. Three treatment-related deaths occurred: 2 patients in the surgical arms (one late pulmonary toxicity and one pulmonary embolus), and 1 patient in the radiation arm (radiation pneumonitis). Induction chemotherapy was completed in 78% of the patients. Complete resection was performed in 73% of 26 patients undergoing thoracotomy. Consolidation chemotherapy was completed in 75% of the patients. No statistically significant difference was found among the treatment arms. The overall progression-free survival rate was 53% at 1 year and 17% at 3 years. The median progression-free survival was 14 months. No difference in the 1-year survival rate (70% vs. 66%) or median survival time (19.4 vs. 17.4 months) between the surgery and RT arms. The median survival in the patients receiving induction chemotherapy only was 8.9 months. Mitomycin-C had no impact on survival (p = 0.75). No statistically significant difference was noted in the time to local failure between the surgical and RT arms. CONCLUSION: The patient accrual to this trial made its results inconclusive, but several observations are notable. In this trial, histologic confirmation of N2 disease in the surgical and nonsurgical arms eliminated the usual biases from clinical staging. In this setting, local control and survival were essentially equal between the surgical and RT arms. The 3- and 5-year survival rates of nonsurgical therapy were comparable to published surgical trials of N2 disease.

Impact of institutional experience on survival outcome of patients undergoing combined chemoradiation therapy for inoperable non-small-cell lung cancer.

PURPOSE: Clinical experience of both physicians and institutions has been shown to significantly influence the outcome of patients. We conducted this retrospective cohort study to examine its impact on the outcome of patients undergoing combined chemoradiation therapy for the treatment of locally advanced inoperable non-small-cell lung cancer. METHODS AND MATERIALS: We compared the clinical data from 239 patients who were enrolled in two consecutive Radiation Therapy Oncology Group (RTOG) trials (RTOG 91-06, RTOG 92-04) according to the number of patients enrolled from each institution in either trial alone or the two trials combined. RESULTS: Overall, patients treated at the institutions that enrolled > or = 5 patients survived longer than those treated at the institutions that enrolled <5 patients (median survival 20.5 vs. 13.4 months, p = 0.0006) with a more than doubling of the 2- and 3-year survival rates (45% and 31% vs. 20% and 13%, respectively). Multivariate analyses confirmed that the number of patients enrolled from each institution was an important prognostic factor for the entire group (p = 0.001) and also for RTOG 91-06 (p = 0.05) and RTOG 92-04 (p = 0.004) when the data were analyzed separately. CONCLUSION: Institutional experience has a significant impact on the survival outcome of patients undergoing combined chemoradiation therapy for inoperable non-small cell lung cancer.

Assessment of quality of life and oral function of patients participating in a phase II study of radioprotection of oral and pharyngeal mucosa by the prostaglandin E(1) analog misoprostol (RTOG 96-07).

PURPOSE: The oral complications associated with radiotherapy to the head and neck are a significant dose-limiting factor. The goals of this study were to determine whether oropharyngeal rinsing and ingestion of misoprostol protect mucous membranes from the acute effects of irradiation, and to evaluate the quality-of-life (QOL) outcomes of patients receiving misoprostol. We report the results of the QOL outcomes of patients in this study. METHODS AND MATERIALS: A total of 33 patients with resected or intact cancer of the oral cavity, oropharynx, supraglottic larynx, or hypopharynx were registered to receive postoperative radiotherapy plus misoprostol or primary radiotherapy plus misoprostol. All patients were scheduled to receive 60-70 Gy at 2 Gy/d within 6-7 weeks. QOL and function were evaluated. RESULTS: A decrease in the QOL and function occurred in all areas covered by the questionnaire at the 6-week interval. This decrease was significant for eating, saliva, taste, and mucous. Of these significant factors, taste, saliva, and mucous consistency had not resolved by 12 weeks. CONCLUSION: Increased understanding of the impact of treatment on QOL and symptoms will formulate the rational design of toxicity interventions and enhance the multidisciplinary care of head-and-neck patients.

A phase III comparison of radiation therapy with or without recombinant beta-interferon for poor-risk patients with locally advanced non-small-cell lung cancer (RTOG 93-04).

PURPOSE: The results of Phase I/II data testing beta-interferon with radiation therapy in a non-small-cell lung cancer population were promising. Based on these data, the Radiation Therapy Oncology Group (RTOG) initiated a Phase III trial to test the efficacy of beta-interferon in poor-risk patients with Stages IIIA and IIIB non-small-cell lung carcinoma. METHODS: Between September 1994 and March 1998, 123 patients were accrued to this trial. Enrolled patients were not eligible for other chemoradiation studies within the RTOG. Eligibility criteria included histologically confirmed Stage IIIA or IIIB non-small-cell lung cancer (according to American Joint Committee on Cancer) considered clinically inoperable or unresectable at the time of surgery. Patients were required to have a Karnofsky performance status 50-70 or >70 and at least 5% weight loss over the preceding 3 months. Betaseron (recombinant human interferon beta(ser), rHuIFN-beta(ser),) was the chosen preparation of beta-interferon. The patients randomized to the investigational arm received 16 x 10(6) IU of Betaseron by i.v. bolus given 3 days a week (Monday-Wednesday) on Weeks 1, 3, and 5. The Betaseron was given 30 minutes before radiation therapy for a total of nine doses. Irradiation was delivered at 2 Gy per fraction, 5 days a week, for a total of 60 Gy over 6 weeks and was identical for both arms. The primary end point of the trial was overall survival with local control as a secondary end point. Toxicities occurring within 90 days of therapy completion were defined as acute. RESULTS: The median follow-up was 4 years (range: 2.5-6 years) for surviving patients. Seventy-six percent of all patients completed beta-interferon. Toxicity was the primary reason for noncompliance. Radiotherapy (RT) compliance was excellent in the RT-alone arm, with 94% completing therapy, compared to 82% in the beta-interferon arm (p = 0.0475). Grade 3 and 4 acute toxicities were higher on the beta-interferon arm (p = 0.0249). Grade 3 and 4 acute toxicities were primarily related to lung (n = 8) and esophagus (n = 7). No Grade 4 or 5 late toxicities were seen for patients in the radiation-alone arm. However, three patients on the beta-interferon arm experienced Grade 4 toxicity, and one patient died. The 1-year survival rate for the RT-alone arm was 44% with a median survival time of 9.5 months. The 1-year survival on the beta-interferon arm was 42% with a median survival of 10.3 months. There was no statistical difference in survival times (p = 0.66). CONCLUSIONS: This multicenter, controlled Phase III trial failed to confirm the efficacy of Betaseron in patients receiving definitive radiotherapy for locally advanced, nonmetastatic non-small-cell lung cancer. The use of beta-interferon led to greater rates of both acute and late treatment-related toxicity. The RTOG continues to investigate other biologic modifiers that may provide a nontoxic alternative for this poor-risk population.

Feasibility of neurocognitive outcome evaluations in patients with brain metastases in a multi-institutional cooperative group setting: results of Radiation Therapy Oncology Group trial BR-0018.

PURPOSE: A multi-institutional trial was conducted by the Radiation Therapy Oncology Group (RTOG) to test the feasibility of performing a test battery consisting of five neurocognitive measures and a quality-of-life instrument in patients with brain metastases. METHODS AND MATERIALS: The major eligibility requirements included histologic proof of a primary malignancy, measurable single or multiple brain metastases, Zubrod performance status of 0-1, neurologic function status of 0-2, and "certification" for administration of neurocognitive assessments. This certification process required either attendance at an RTOG neurocognitive assessment training workshop or review of an instructional video, followed by submission of an audiotape of mock/simulated test sessions for central review. The test battery included the following measures: the Mini-Mental Status Examination, Hopkins Verbal Learning Test, Verbal Fluency/Controlled Word Association Test, Ruff 2 and 7 test, Trailmaking Test, and Profile of Mood States-Short Form. The primary objective of this trial was to establish whether patients were able to complete this test battery. Compliance was defined as successful completion of a test measure. The test battery was to be administered just before, at completion of, and 1 month after whole brain radiotherapy to 37.5 Gy at 2.5 Gy/fraction once daily. Fifty-nine patients were enrolled in the trial. RESULTS: The patient characteristics included 32% > or =65 years; 44% with Zubrod performance status of 0; and 81% with multiple brain metastases. The overall compliance rate for administration and completion of the five neurocognitive measures and a quality-of-life instrument before treatment, at treatment completion, and 1 month after treatment was > or =95%, > or =84%, and > or =70%. The most common causes of noncompliance were patient-related factors (e.g., performance status or inability to understand test instructions) and not institutional error. CONCLUSION: Neurocognitive evaluation of patients with brain metastases in a multi-institutional and cooperative group setting is feasible using the test battery and certification process used in this study. This battery and certification process will be incorporated into future RTOG brain tumor trials.

Vitamin D intake is inadequate in spinal muscular atrophy type I cohort: correlations with bone health.

Children with type I spinal muscular atrophy commonly demonstrate reduced bone mineral density. Our objectives were to evaluate and assess adequacy of vitamin D intake, serum levels, and association with bone mineral density. Assessments were completed using 3-day food records and dual energy x-ray absorptiometry scans. The spinal muscular atrophy type I cohort included 22 males and 18 females (N = 40), with a mean age of 18.6 months. Data collection occurred from 2001 to 2011. Seventy-five percent of patients had inadequate intake of vitamin D at the initial visit. Using mixed-effects analyses, vitamin D and calcium intakes correlated positively with bone mineral density (r = 0.31 and r = 0.53, respectively). Increased vitamin D and calcium consumption were associated with an increase in bone mineral density (P = .04 and P = .01, respectively). Vitamin D intake correlated positively with serum levels (r = 0.65). Further study is needed to determine optimal intakes of vitamin D and calcium in the spinal muscular atrophy type I population.

SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy.

BACKGROUND: Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and L-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2-8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children. METHODS: This study involved 33 genetically proven type 3 SMA subjects ages 3-17 years. Subjects underwent two baseline assessments over 4-6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores. RESULTS: Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful. CONCLUSIONS: This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. TRIAL REGSITRATION: Clinicaltrials.gov NCT00227266.

SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy.

BACKGROUND: Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo. METHODS: Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1) and an ambulatory group of "walkers" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures. RESULTS: At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007). CONCLUSIONS: This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials. TRIAL REGISTRY: Clinicaltrials.gov NCT00227266.

Phase II open label study of valproic acid in spinal muscular atrophy.

UNLABELLED: Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p

Can serum markers be used to predict acute and late toxicity in patients with lung cancer? Analysis of RTOG 91-03.

PURPOSE: To identify factors that are predictive of satisfactory acute and long-term pulmonary tolerance of definitive irradiation and, conversely, factors that are predictive of excessive impairment of pulmonary functions. To determine if there is any correlation between early elevation of biochemical markers obtained in blood of irradiated patients and subsequent pulmonary abnormalities as detected by clinical findings, pulmonary function tests, and/or radiographic findings of pneumonitis/fibrosis. MATERIALS AND METHODS: This was a multi-institutional prospective trial sponsored by the Radiation Therapy Oncology Group. Eligible patients had surgically unresectable or medically inoperable stage II or III non-small cell lung cancer. Pretreatment evaluation included baseline dyspnea index (BDI) and pulmonary function tests (PFT). Radiation therapy consisted of once-daily treatment with 2 Gy to a total of 60 to 66 Gy. A quantitative nuclear medicine perfusion study was correlated to the radiation therapy portals to assess the proportion of lung irradiated. Blood for serum markers (surfactant apoprotein, procollagen type III, interleukin [IL]-1, interleukin-6, and tumor necrosis factor-alpha) was drawn prior to the beginning of radiation therapy and then weekly during treatment (at 10, 20, 30, 40, 50, and 60 Gy). Post-treatment follow-up included PFT every 3 months for 1 year and then annually. The BDI was reevaluated at the same intervals. RESULTS: There were 127 analyzable patients. Squamous cell carcinoma was the predominant histology and 93% of the patients had AJCC stage III disease. The median survival time is 10.9 months with 43% of patients living 1 year and 10% living 3 years. Grade >or=2 acute lung toxicity was seen in 18% of patients; patients least likely to develop lung toxicity are those with undetectable levels of IL-6 at 10 Gy and diffusing capacity of the lung for carbon monoxide percent (DLCO%) >54. Patients most likely to develop acute toxicity are those with elevated IL-6 and age >60 years. Grade >or=2 late lung toxicity was seen in 30% of patients. Karnofsky performance status was the only pretreatment factor predictive of late lung toxicity. The proportion of lung within the irradiated field, BDI indices, physician-assessed baseline dyspnea, and baseline PFT were not predictive of pulmonary toxicity. Using grade >or=2 toxicity as an event, age >60 years, gender, and a surfactant level <797 at 20 Gy were predictive of late lung toxicity. CONCLUSIONS: Elevated levels of serum IL-6 after 10 Gy of lung irradiation appear to predict grade >or=2 acute lung toxicity, and high serum levels of surfactant apoproteins at 20 Gy correlated with grade >or=2 late pulmonary toxicity. These findings need to be confirmed but could be useful in a model to predict risk of pulmonary injury with high doses of radiation. For future studies, it is necessary to evaluate serum markers at multiple time-points during treatment, and quality control is critical during the collection, storage, and analysis of these serum markers.

Natural history of denervation in SMA: relation to age, SMN2 copy number, and function.

Denervation was assessed in 89 spinal muscular atrophy (SMA) 1, 2, and 3 subjects via motor unit number estimation (MUNE) and maximum compound motor action potential amplitude (CMAP) studies, and results correlated with SMN2 copy, age, and function. MUNE and maximum CMAP values were distinct among SMA subtypes (p < 0.05). Changes in MUNE and maximum CMAP values over time were dependent on age, SMA type, and SMN2 copy number. SMN2 copy number less than 3 correlated with lower MUNE and maximum CMAP values (p < 0.0001) and worse functional outcomes. As SMN2 copy number increases, so does functional status (p < 0.0001). Change in MUNE longitudinally over the time intervals examined in this study was not statistically significant for any SMA cohort. However, a decline in maximum CMAP over time was apparent in SMA2 subjects (p = 0.049). Age-dependent decline in MUNE and maximum CMAP was apparent in both SMA 1 (p < 0.0001) and SMA 2 (p < 0.0001) subjects, with age as an independent factor regardless of type. Maximum CMAP at the time of the initial assessment was most predictive of functional outcome (p < 0.0001). Prospective longitudinal studies in four prenatally diagnosed infants demonstrated significant progressive denervation in association with symptomatic onset or functional decline. These data highlight the potential value of such measures in increasing our understanding of pathophysiological factors involved in denervation in SMA.