Phase 1 trial of olaratumab monotherapy and in combination with chemotherapy in pediatric patients with relapsed/refractory solid and central nervous system tumors.

Olaratumab is a monoclonal antibody that specifically binds to platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21-day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide by investigator choice for subsequent 21-day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A-C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose-limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma-glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment-emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.

Circulating Tumor Cells and Biomarker Modulation with Olaratumab Monotherapy Followed by Olaratumab plus Doxorubicin: Phase Ib Study in Patients with Soft-Tissue Sarcoma.

This phase Ib study enumerated whole blood circulating tumor cells (CTC) and evaluated biomarkers in patients with potentially resectable soft-tissue sarcoma (STS) treated with olaratumab monotherapy (20 mg/kg) for one cycle followed by up to six cycles of olaratumab (20 mg/kg, cycles 1-2; 15 mg/kg, cycles 3-7) plus doxorubicin (75 mg/m2 on day 1). CTCs, platelet-derived growth factor receptors (PDGFR), and PDGF ligand expression in tumor tissue pre- and post-olaratumab monotherapy were evaluated. Antitumor activity, safety, pharmacokinetics, and PET/biomarker association with clinical outcome were assessed. Of 51 treated patients, 35, 43, and 37 were evaluable for CTC enumeration, PDGFRs, and PDGF ligand expression, respectively. An increase in CTCs at cycle 1 day 8 was observed, followed by a significant reduction by cycle 3 day 1 or 30-day follow-up. Decrease in CTC counts after olaratumab monotherapy was higher in patients with disease control than without disease control (57.9% vs. 31.2%). Baseline IHC expression was positive in most patients for PDGFRα [n = 31 (72.1%)] and PDGFRß [n = 36 (83.7%)]. Similar rates were observed post-olaratumab monotherapy [PDGFRα, n = 30 (69.8%); PDGFRß, n = 33 (76.7%)]. Eleven patients (29.7%) showed a 30% reduction by RT-PCR in PDGFRα at cycle 2. PDGFR expression and PET response showed no correlation with clinical outcome. Safety and pharmacokinetic profiles were consistent with previous reports. This study, the first to use a validated method for CTC detection, confirms that CTC enumeration in STS is feasible. However, no correlation was observed between PDGFRα expression and clinical outcome.

Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis.

BACKGROUND: Asparaginase, an agent used in the treatment of acute lymphoblastic leukemia (ALL), is associated with the development of pancreatitis. The clinical course and long-term outcome of patients experiencing this complication has not been extensively detailed. PROCEDURE: We reviewed the clinical course for all children with ALL diagnosed with pancreatitis at the Dana-Farber Cancer Institute/Children's Hospital Boston between 1987 and 2003. The outcome of these patients was compared with that of patients with ALL who did not experience pancreatitis. RESULTS: Twenty-eight of 403 children (7%) were diagnosed with pancreatitis. Patients 10-18 years old at diagnosis had 2.4 times the risk of developing pancreatitis compared with younger patients. Pancreatitis typically occurred early in the course of therapy (median 4 weeks after first dose of asparaginase). Ninety-three percent of affected patients were hospitalized and 57% received parenteral nutrition. No patient developed chronic sequelae or died as a result of pancreatitis. Sixteen (57%) patients were re-treated with asparaginase, 10 of whom had another episode of pancreatitis. No significant differences in event-free survival were observed when comparing patients with and without a history of pancreatitis. CONCLUSION: Asparaginase-associated pancreatitis was more common in older children, and caused significant acute morbidity. It tended to occur after the first few doses of asparaginase, suggesting a predisposition to this complication rather than a cumulative drug effect. Re-treatment with asparaginase after an episode of pancreatitis was associated with a high risk of recurrent pancreatitis.

Risk stratification for biochemical recurrence in men with positive surgical margins or extracapsular disease after radical prostatectomy: results from the SEARCH database.

PURPOSE: In men with extracapsular disease or positive surgical margins after radical prostatectomy immediate adjuvant therapy decreases the risk of biochemical recurrence at the cost of increased toxicity. We further stratified these men into a low risk group in which watchful waiting after surgery may be preferred and a high risk cohort in which adjuvant therapy may be preferred. MATERIALS AND METHODS: We performed a retrospective analysis of the records of 902 men treated with radical prostatectomy in the Shared Equal-Access Regional Cancer Hospital (SEARCH) database between 1988 and 2007 with positive surgical margins and/or extracapsular disease without seminal vesicle invasion or lymph node metastasis. The significant independent predictors of biochemical recurrence were determined using a multivariate Cox proportional hazards model. Based on the recurrence risk generated from the multivariate Cox proportional hazards regression model we generated tables to estimate the risk of recurrence-free survival 1, 3 and 5 years after surgery. RESULTS: At a median of 3 years of followup 346 patients (39%) had biochemical recurrence. On multivariate analysis the significant predictors of biochemical recurrence were age more than 60 years, prostate specific antigen more than 10 ng/ml, Gleason score 4 + 3 and 8-10, 2 or more sites of positive surgical margins and prostate specimen weight 30 gm or less. As determined by the concordance index, the overall predictive accuracy of the model was 0.67, while it was 0.60 for the postoperative Kattan nomogram in this patient population. CONCLUSIONS: We have developed a simple instrument that, once validated, may aid in the postoperative decision making process for men at intermediate risk for recurrence after prostatectomy.

The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia.

BACKGROUND: Doxorubicin chemotherapy is very effective in children with acute lymphoblastic leukemia (ALL) but also injures myocardial cells. Dexrazoxane, a free-radical scavenger, may protect the heart from doxorubicin-associated damage. METHODS: To determine whether dexrazoxane decreases doxorubicin-associated injury of cardiomyocytes, we randomly assigned 101 children with ALL to receive doxorubicin alone (30 mg per square meter of body-surface area every three weeks for 10 doses) and 105 to receive dexrazoxane (300 mg per square meter) followed immediately by doxorubicin. Serial measurements of serum cardiac troponin T were obtained in 76 of 101 patients in the doxorubicin group and 82 of 105 patients in the group given dexrazoxane and doxorubicin. A total of 2377 serum samples (mean, 15.1 samples per patient) were obtained before, during, and after treatment with doxorubicin. Troponin T levels were evaluated in a blinded fashion to determine whether they were elevated (>0.01 ng per milliliter)--the primary end point--or extremely elevated (>0.025 ng per milliliter). RESULTS: Elevations of troponin T occurred in 35 percent of the patients (55 of 158). Patients treated with doxorubicin alone were more likely than those who received dexrazoxane and doxorubicin to have elevated troponin T levels (50 percent vs. 21 percent, P<0.001) and extremely elevated troponin T levels (32 percent vs. 10 percent, P<0.001). The median follow-up was 2.7 years. The rate of event-free survival at 2.5 years was 83 percent in both groups (P=0.87 by the log-rank test). CONCLUSIONS: Dexrazoxane prevents or reduces cardiac injury, as reflected by elevations in troponin T, that is associated with the use of doxorubicin for childhood ALL without compromising the antileukemic efficacy of doxorubicin. Longer follow-up will be necessary to determine the influence of dexrazoxane on echocardiographic findings at four years and on event-free survival.

Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma.

PURPOSE: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFalpha). PATIENTS AND METHODS: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. RESULTS: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. CONCLUSION: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.

Topotecan is an active agent in the first-line treatment of metastatic or recurrent endometrial carcinoma: Eastern Cooperative Oncology Group Study E3E93.

PURPOSE: To determine the clinical activity and the toxicity profile of the topoisomerase-I inhibitor, topotecan, in women with recurrent or advanced endometrial carcinoma. PATIENTS AND METHODS: A prospective, phase II clinical trial was initiated by the Eastern Cooperative Oncology Group (ECOG). Patients had histologically confirmed advanced or recurrent endometrial carcinoma, measurable disease, no prior cytotoxic therapy, an ECOG performance status of 0 to 2, and evidence of disease progression while on progestins or after radiation therapy. Topotecan was administered at 1.5 mg/m(2) (or 1.2 mg/m(2) for patients with prior pelvic radiation) intravenously daily for 5 days every 3 weeks. RESULTS: A total of 44 patients were enrolled; 42 were eligible. The study was suspended because of unexpected toxicities, primarily sepsis and bleeding. After toxicity review, the study was reopened using lower doses of topotecan (1.0 mg/m(2) or 0.8 mg/m(2) for patients with prior radiation therapy). In addition, prophylactic use of growth factors was allowed after the first cycle, and patients with performance status of 2 were excluded. The major toxicities were hematologic and gastrointestinal. Among the 40 assessable patients, there were three (7.5%) complete responders and five partial responders (12.5%), for an overall response rate of 20%. The median duration of response was 8.0 months and of overall survival was 6.5 months. CONCLUSION: Topotecan is an active agent for the treatment of advanced endometrial carcinoma. At the doses and schedules initially used, toxicities were unacceptable; however, at the modified doses, toxicities were acceptable and clinical activity was preserved.

Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience.

PURPOSE: T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10% to 15% of newly diagnosed cases of childhood acute lymphoblastic leukemia (ALL). Historically, T-ALL patients have had a worse prognosis than other ALL patients. PATIENTS AND METHODS: We reviewed the outcomes of 125 patients with T-ALL treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium trials between 1981 and 1995. Therapy included four- or five-agent remission induction; consolidation therapy with doxorubicin, vincristine, corticosteroid, mercaptopurine, and weekly high-dose asparaginase; and cranial radiation. T-ALL patients were treated the same as high-risk B-progenitor ALL patients. Fifteen patients with T-cell lymphoblastic lymphoma were also treated with the same high-risk regimen between 1981 and 2000. RESULTS: The 5-year event-free survival (EFS) rate for T-ALL patients was 75% +/- 4%. Fourteen of 15 patients with T-cell lymphoblastic lymphoma were long-term survivors. There was no significant difference in EFS comparing patients with T-ALL and B-progenitor ALL (P =.56), although T-ALL patients had significantly higher rates of induction failure (P <.0001), and central nervous system (CNS) relapse (P =.02). The median time to relapse in T-ALL patients was 1.2 years versus 2.5 years in B-progenitor ALL patients (P =.001). There were no pretreatment characteristics associated with worse prognosis in patients with T-ALL. CONCLUSION: T-ALL patients fared as well as B-progenitor patients on DFCI ALL Consortium protocols. Patients with T-ALL remain at increased risk for induction failure, early relapse, and isolated CNS relapse. Future studies should focus on the identification of and treatment for T-ALL patients at high risk for treatment failure.

Outcomes of a randomized trial of hyperfractionated cranial radiation therapy for treatment of high-risk acute lymphoblastic leukemia: therapeutic efficacy and neurotoxicity.

PURPOSE: We evaluated 8-year survival and late neuropsychologic toxicity in children with acute lymphoblastic leukemia treated in a randomized clinical trial to test whether hyperfractionated (twice daily) cranial radiation therapy (CRT) can reduce incidence and severity of late toxicities associated with 18 Gy of CRT. PATIENTS AND METHODS: Between 1987 and 1995, 369 children treated on two consecutive Dana-Farber Cancer Institute Consortium protocols for high-risk acute lymphoblastic leukemia were randomly assigned to conventionally fractionated CRT (CFX) or hyperfractionated CRT (HFX) to a total dose of 18 Gy. Neuropsychologic testing was completed for 125 of 287 children in continuous complete remission. Event-free and overall survival, as well as neuropsychologic function, were compared for the two arms of the protocol. RESULTS: Eight-year event-free survival (+/- SE) was 80% +/- 3% for children randomly assigned to CFX and 72% +/- 3% for HFX (P =.06). Overall survival was 85% +/- 3% for CFX and 78% +/- 3% for HFX (P =.06). CNS relapses occurred in 2.8% of patients receiving CFX and 2.7% receiving HFX (P =.99). Cognitive function for both groups was solidly in the average range, with no group differences in intelligence, academic achievement, visuospatial reasoning, or verbal learning. Children on the HFX arm exhibited a modest advantage for visual memory (P <.05). CONCLUSION: HFX provides no benefit in terms of cognitive late effects and may compromise antileukemic efficacy. HFX should not be substituted for conventionally dosed CRT in children who require radiation therapy for treatment of acute lymphoblastic leukemia.

Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia.

The Dana-Farber Cancer Institute (DFCI) Childhood ALL Consortium Protocol 95-01 was designed to minimize therapy-related morbidity for children with newly diagnosed ALL without compromising efficacy. Patients participated in randomized comparisons of (1) doxorubicin given with or without dexrazoxane, a cardioprotectant (high-risk patients), (2) intensive intrathecal chemotherapy and cranial radiation (standard-risk patients), and (3) Erwinia and Escherichia coli asparaginase (all patients). Between 1996 and 2000, 491 patients (aged 0-18 years) were enrolled (272 standard risk and 219 high risk). With a median of 5.7 years of follow-up, the estimated 5-year event-free survival (EFS) for all patients was 82%+/-2%. Dexrazoxane did not have a significant impact on the 5-year EFS of high-risk patients (P=.99), and there was no significant difference in outcome of standard-risk patients based on type of central nervous system (CNS) treatment (P=.26). Compared with E coli asparaginase, Erwinia asparaginase was associated with a lower incidence of toxicity (10% versus 24%), but also an inferior 5-year EFS (78%+/-4% versus 89%+/-3%, P=.01). We conclude that (1) dexrazoxane does not interfere with the antileukemic effect of doxorubicin, (2) intensive intrathecal chemotherapy is as effective as cranial radiation in preventing CNS relapse in standard-risk patients, and (3) once-weekly Erwinia is less toxic than E coli asparaginase, but also less efficacious.

EGFR dinucleotide repeat polymorphism as a prognostic indicator in non-small cell lung cancer.

BACKGROUND: The epidermal growth factor receptor (EGFR) has been implicated in tumor growth and progression. Intron 1 of the EGFR gene contains a polymorphic simple sequence repeat (SSR) of 14 to 21 CA dinucleotides, the length of which correlates inversely with the level of EGFR transcription. The authors hypothesized that a shorter length of tumor SSR would be associated with poorer survival in patients with non-small cell lung cancer (NSCLC). METHODS: Patients enrolled in Eastern Cooperative Oncology Group E3590 (a randomized, prospective trial of adjuvant therapy following resection of stages II and IIIa NSCLC) were randomized to radiation or radiation plus chemotherapy. Genomic DNA extracted from resected tumors was amplified for EGFR intron 1 by polymerase chain reaction and sequenced in a 3730XL DNA analyzer. RESULTS: One hundred fifty-seven primary tumors were sequenced, 106 (68%) of which were heterozygous for intron 1. The most common genotypes were allele lengths of 17/19 dinucleotides (17.8%), 17/18 (11.4%), and 19/19 (11.4%). Allele status (homozygous versus heterozygous) did not correlate with race, gender, weight, performance status, histology, stage, or survival. Shorter allele length (< or =18 versus >18 CA dinucleotide repeats) was associated with squamous cell histology (p = 0.03). Allele sum of greater than 35 was associated with improved overall survival (log-rank p = 0.03, hazard ratio = 0.66). CONCLUSION: This is the first study to characterize the EGFR intron 1 SSR polymorphism in NSCLC. Tumors were most commonly heterozygous for SSR length. Squamous histology was associated with a shorter SSR. Longer sequences are associated with improved survival.

Phase II study of gemcitabine in combination with docetaxel in patients with advanced pancreatic carcinoma (E1298). A trial of the eastern cooperative oncology group.

BACKGROUND: Responses have been observed in several studies of docetaxel as treatment for advanced pancreatic carcinoma. This trial was designed to determine if the addition of docetaxel to gemcitabine therapy produced responses in >/=25% of patients with chemonaive advanced pancreatic cancer. PATIENTS AND METHODS: This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients received docetaxel 75 mg/m(2) i.v. over 1 h followed by gemcitabine 2,000 mg/m(2) biweekly until progression or intolerable toxicity. The primary endpoint of the trial was to determine the objective response rate with secondary endpoints of progression-free survival and overall survival. RESULTS: Out of the 32 eligible patients, 2 patients had a complete response and 2 patients had a partial response for an observed objective response rate of 12.5% (90% CI: 4.4, 26.4%). Median survival was 4.7 months. Most toxicities were hematologic, with 48% of patients experiencing grade 4 toxicity. CONCLUSIONS: The confirmed complete response rate of 6% and partial response rate of 6% is encouraging, but the toxicity of this regimen appears significant. Based upon these results, this combination of gemcitabine and docetaxel is not worthy of further study. Different schedules and dosages may be more promising.

Phase II study of interferon gamma in malignant carcinoid tumors (E9292): a trial of the Eastern Cooperative Oncology Group.

PURPOSE: To determine the safety and efficacy of treatment with gamma interferon (IFNgamma) in patients with metastatic carcinoid tumor. PATIENTS AND METHODS: 51 patients were enrolled on this Phase II Eastern Cooperative Oncology Group (ECOG) study. Seventy five percent of them had hormonally active tumors. Treatment consisted of IFNgamma subcutaneously at a daily dose of 0.1 mg/m(2). Patents were evaluated for toxicity weekly for the first month and monthly thereafter; response was determined radiologically every 8 weeks. RESULTS: Patients received treatment with IFNgamma for a median of 17.9 weeks (range 2-175). Toxicity was generally mild and expected: 61% experienced noninfected fever and 21% developed granulocytopenia. Three patients (6%) had a partial response; there were no complete responses. Median time to progression was 5.5 months (95% confidence interval 3.9-11.1). The 1-year progression free rate was 28% (13.4-43.4%). Median survival was 42 months, with a 1-year survival rate of 67% (53.3-80%). DISCUSSION: This Phase II study demonstrated that therapy with IFNgamma in patients with metastatic carcinoid tumor was well-tolerated, but did not produce significant antitumor effects. The overall results were somewhat comparable to those previously seen with alpha interferons as well as cytotoxic drugs.