Guy Gammon

Prolonged Survival After Complete Resection of Disseminated Melanoma and Active Immunotherapy With a Therapeutic Cancer Vaccine

PURPOSEnThe curative effect of surgery in certain patients with metastatic melanoma suggests the presence of endogenous antitumor responses. Because melanoma is immunogenic, we investigated whether a therapeutic cancer vaccine called Canvaxin (CancerVax Corporation, Carlsbad, CA) could enhance antitumor immune responses and thereby prolong survival.nnnPATIENTS AND METHODSnOf 263 patients who underwent complete resection of American Joint Committee on Cancer stage IV melanoma, 150 received postoperative adjuvant vaccine therapy and 113 did not. The overall survival (OS) for the two groups was compared by Cox regression. Further survival analysis was performed by matched-pair analysis according to three prognostic variables: sex, metastatic site, and number of tumor-involved organ sites.nnnRESULTSnFive-year OS rates were 39% for vaccine and 19% for nonvaccine patients. On multivariate analysis, vaccine therapy was the most significant prognostic variable in this cohort (P =.0001). Analysis of 107 matched pairs of vaccine and nonvaccine patients revealed a significant OS advantage for vaccine therapy (P =.0009): 5-year OS was 39% for vaccine patients versus 20% for nonvaccine patients. There was a significant delayed-type hypersensitivity (DTH) response to adjuvant vaccine therapy (P =.0001), and OS was significantly correlated with DTH to vaccine (P =.0001) but not with DTH to purified protein derivative (PPD), a control antigen.nnnCONCLUSIONnProlonged survival was observed in patients who received postoperative active immunotherapy with Canvaxin therapeutic cancer vaccine. The correlation of survival with vaccine-DTH responses but not PPD-DTH indicates a treatment-specific effect. These findings suggest that adjuvant active specific immunotherapy should be considered after cytoreductive surgery for advanced melanoma.

Phase I Study of Quizartinib Administered Daily to Patients With Relapsed or Refractory Acute Myeloid Leukemia Irrespective of FMS-Like Tyrosine Kinase 3–Internal Tandem Duplication Status

PURPOSEnFMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity in preclinical AML models.nnnPATIENTS AND METHODSnQuizartinib was administered orally at escalating doses of 12 to 450 mg/day to 76 patients (median age, 60 years; range, 23 to 86 years; with a median of three prior therapies [range, 0 to 12 therapies]), enrolled irrespective of FLT3-ITD mutation status in a phase I, first-in-human study in relapsed or refractory AML.nnnRESULTSnResponses occurred in 23 (30%) of 76 patients, including 10 (13%) complete remissions (CR) of any type (two CRs, three CRs with incomplete platelet recovery [CRp], five CRs with incomplete hematologic recovery [CRi]) and 13 (17%) with partial remissions (PRs). Of 17 FLT3-ITD-positive patients, nine responded (53%; one CR, one CRp, two CRis, five PRs); of 37 FLT3-ITD-negative patients, five responded (14%; two CRps, three PRs); of 22 with FLT3-ITD-indeterminate/not tested status, nine responded (41%; one CR, three CRis, five PRs). Median duration of response was 13.3 weeks; median survival was 14.0 weeks. The most common drug-related adverse events (> 10% incidence) were nausea (16%), prolonged QT interval (12%), vomiting (11%), and dysgeusia (11%); most were ≤ grade 2. The maximum-tolerated dose was 200 mg/day, and the dose-limiting toxicity was grade 3 QT prolongation. FLT3-ITD phosphorylation was completely inhibited in an in vitro plasma inhibitory assay.nnnCONCLUSIONnQuizartinib has clinical activity in patients with relapsed/refractory AML, particularly those with FLT3-ITD, and is associated with an acceptable toxicity profile.

Prolonged survival of patients receiving active immunotherapy with Canvaxin therapeutic polyvalent vaccine after complete resection of melanoma metastatic to regional lymph nodes.

ObjectiveTo determine whether adjuvant postoperative active specific immunotherapy with a therapeutic polyvalent vaccine (PV) called Canvaxin can prolong survival following complete resection of melanoma metastatic to regional nodes (American Joint Committee on Cancer [AJCC] stage III melanoma). Summary Background DataDespite complete lymphadenectomy, 5-year overall survival (OS) for patients with melanoma metastatic to regional lymph nodes is only 20% to 50%, depending on the number of tumor-involved nodes. In 1984, the authors began phase II trials of Canvaxin PV as postsurgical adjuvant therapy for AJCC stage III melanoma. MethodsPatients who received PV between 1984 and 1998 were compared with patients who did not receive PV postsurgical therapy between 1971 and 1998. The seven covariates recently defined by the AJCC Melanoma Staging Committee (number of metastatic nodes, palpable status, ulceration, age, primary site, pT stage, and gender) were included by Cox regression in a multivariate model of OS. A computerized program matched PV and non-PV patients by these covariates. ResultsOf 2,602 patients who underwent complete lymphadenectomy for AJCC stage III melanoma with regional nodal metastases and were followed up by the same team of oncologists between 1971 and 1998, 935 received PV and 1,667 did not. Median OS and 5-year OS were significantly higher in PV than non-PV patients (56.4 vs. 31.9 months and 49% vs. 37%, respectively;P = .0001). When the non-PV patients were matched by the four most significant covariates, 447 matched pairs were formed between patients seen before or after January 1, 1985, and the OS was not different between the two time periods (P = .789). However, when the PV patients were matched with non-PV patients by six covariates forming 739 pairs, the PV patients survived longer (P = .0001). Detailed analysis of the 1,505 patients who were seen or who began vaccine therapy within 4 months after lymphadenectomy, and who had more complete data on the seven prognostic covariates showed that median OS and 5-year OS were higher in 445 PV patients than in 1,060 non-PV patients: 70.4 versus 31 months and 52% versus 37%, respectively (P = .0001). Multivariate Cox regression analysis identified six significant prognostic factors: number of metastatic nodes, size of metastatic nodes, pT stage, ulceration, age, and PV therapy. PV therapy reduced the relative risk of death to 0.64 (95% confidence interval, 0.55–0.76) (P = .0001); sex and site of primary were of borderline significance. ConclusionsThis large single-institution study independently confirmed the significance of prognostic covariates in the new AJCC staging system. By using modern statistical methods that controlled for all known prognostic factors, it also demonstrated PV’s ability to significantly enhance OS. A multicenter phase III randomized trial is underway to validate the efficacy of PV as a postsurgical adjuvant.

Advantages of Concurrent Biochemotherapy Modified by Decrescendo Interleukin-2, Granulocyte Colony-Stimulating Factor, and Tamoxifen for Patients With Metastatic Melanoma

PURPOSEnConcurrent biochemotherapy results in high response rates but also significant toxicity in patients with metastatic melanoma. We attempted to improve its efficacy and decrease its toxicity by using decrescendo dosing of interleukin-2 (IL-2), posttreatment granulocyte colony-stimulating factor (G-CSF), and low-dose tamoxifen.nnnPATIENTS AND METHODSnForty-five patients with poor prognosis metastatic melanoma were treated at a community hospital inpatient oncology unit affiliated with the John Wayne Cancer Institute (Santa Monica, CA) between July 1995 and September 1997. A 5-day modified concurrent biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo IL-2, interferon alfa-2b, and tamoxifen was repeated at 21-day intervals. G-CSF was administered beginning on day 6 for 7 to 10 days.nnnRESULTSnThe overall response rate was 57% (95% confidence interval, 42% to 72%), the complete response rate was 23%, and the partial response rate was 34%. Complete remissions were achieved in an additional 11% of patients by surgical resection of residual disease after biochemotherapy. The median time to progression was 6.3 months and the median duration of survival was 11.4 months. At a maximum follow-up of 36 months (range, 10 to 36 months), 32% of patients are alive and 14% remain free of disease. Decrescendo IL-2 dosing and administration of G-CSF seemed to reduce toxicity, length of hospital stay, and readmission rates. No patient required intensive care unit monitoring, and there were no treatment-related deaths.nnnCONCLUSIONnThe data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.

Overview of melanoma vaccines: Active specific immunotherapy for melanoma patients

Although a phase III trial has yet to show a statistically significant improvement in the disease-free or overall survival of melanoma patients receiving vaccine therapy, several phase II trials have shown enhanced disease-free and overall survival of patients who develop a humoral and/or cellular response to a melanoma vaccine. The challenge of active specific immunotherapy research is to determine which combination of humoral and cellular immune responses optimizes clinical outcome and how to monitor the immune response effectively. This review identifies key components of a successful melanoma vaccine, discusses new ways to modulate and stimulate the immune system, and summarizes some of the important clinical trials of active specific immunotherapy for patients with melanoma.

Is the survival of melanoma patients receiving polyvalent melanoma cell vaccine linked to the human leukocyte antigen phenotype of patients

PURPOSEnAn allogeneic polyvalent melanoma cell vaccine (PMCV) has been shown to be efficacious in improving overall survival of patients with malignant melanoma in a phase II clinical setting. The PMCV consists of three allogeneic melanoma cell lines. The objectives of the study were to determine (1) whether the survival of melanoma patients who received PMCV was related to the patients human leukocyte antigen (HLA) class I phenotype matching the HLA class I phenotype of the PMCV, and (2) whether PMCV clinical efficacy was correlated to melanoma patients with a particular HLA phenotype(s).nnnMATERIALS AND METHODSnPMCV was given to 69 melanoma patients with American Joint Committee on Cancer (AJCC) stage I to IV disease status. The PMCV and patients lymphocytes were typed for HLA-A and -B. A correlation was made between the HLA expression of PMCV lines and the HLA of patients to their survival status. A second correlation was made between the HLA of patients and survival independent of the PMCV HLA phenotype.nnnRESULTSnPatients whose HLA phenotype (A3/11 and B7/44) matched the PMCV lines had a better overall survival (P < .029). Analysis of HLA expression of patients independent of PMCV HLA to survival showed that HLA-A25 phenotype patients had a significantly better overall survival (P = .006). HLA-B35 patients had a poorer survival outcome (P = .019).nnnCONCLUSIONnThe studies indicate that overall survival following PMCV treatment in melanoma patients significantly correlates with their HLA phenotypes. These correlations may be related to the host immune response to the PMCV or due to differences in the clinical course of melanoma in patients with different HLA types.

Update on active specific immunotherapy with melanoma vaccines

Although a randomized clinical trial has yet to show a statistically significant improvement in the survival of patients receiving vaccine therapy for malignant melanoma, several studies have shown enhanced survival of patients developing an immune response to a melanoma vaccine. The knowledge and techniques of modern molecular biology and immunology suggest multiple strategies to augment this response. The challenge of immunotherapy research is to determine which combination of approaches leads to a favorable clinical response and how to monitor that response effectively. This review identifies components of a successful vaccine, discusses new ways to modulate and stimulate the immune system, and summarizes some of the more interesting clinical trials of melanoma vaccine immunotherapy. J. Surg. Oncol. 1997;66:55–64.

A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study.

Purpose: To determine a safe and biologically active dose of quizartinib (AC220), a potent and selective class III receptor tyrosine kinase (RTK) FLT3 inhibitor, in combination with salvage chemotherapy in children with relapsed acute leukemia. Experimental Design: Quizartinib was administered orally to children with relapsed AML or MLL-rearranged ALL following 5 days of high-dose cytarabine and etoposide (AE). A 3+3 dose escalation design was used to identify a safe and biologically active dose. Plasma inhibitory assay (PIA) testing was performed weekly to determine biologic activity. Results: Toxicities were consistent with intensive relapsed leukemia regimens. One of 6 patients experienced a dose-limiting toxicity (DLT) at 40 mg/m2/day (elevated lipase) and 1 of 9 had a DLT (hyperbilirubinemia) at the highest tested dose of 60 mg/m2/day. Of 17 response evaluable patients, 2 had complete response (CR), 1 complete response without platelet recovery (CRp), 1 complete response with incomplete neutrophil and platelet recovery (CRi), 10 stable disease (SD), and 3 progressive disease (PD). Of 7 FLT3-ITD patients, 1 achieved CR, 1 CRp, 1 Cri, and 4 SD. FLT3-ITD patients, but not FLT3 wild-type (WT) patients, had significantly lower blast counts post-quizartinib. FLT3 phosphorylation was completely inhibited in all patients. Conclusions: Quizartinib plus intensive chemotherapy is well tolerated at 60 mg/m2/day with near complete inhibition of FLT3 phosphorylation in all patients. The favorable toxicity profile, pharmacodynamic activity, and encouraging response rates warrant further testing of quizartinib in children with FLT3-ITD AML. Clin Cancer Res; 22(16); 4014–22. ©2016 AACR.

Results of a phase 1 study of quizartinib as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic stem cell transplant.

FLT3‐ITD–mutated acute myeloid leukemia (AML) has very high risk of relapse and is associated with poor outcome following allogeneic hematopoietic‐cell transplant (allo‐HCT). This two‐part, phase 1, multicenter, open‐label, sequential‐group, dose‐escalation study aimed to determine dose‐limiting toxicities (DLTs), maximum tolerated dose (MTD), and safety/tolerability of quizartinib, a selective and highly potent FLT3 inhibitor, when administered as maintenance therapy after allo‐HCT. Thirteen subjects with documented FLT3‐ITD–mutated AML in morphological remission following allo‐HCT received one of two quizartinib dihydrochloride dose levels (DL): 40 mg/d (DL1; nu2009=u20097) and 60 mg/d (DL2; nu2009=u20096), administered orally in 28‐day cycles for up to 24 cycles. Median age of participants was 43 years. All subjects received human leukocyte antigen (HLA)‐matched allo‐HCT. One subject treated at DL1 and 1 treated at DL2 had DLTs that required drug interruption (grade 3 gastric hemorrhage and grade 3 anemia, respectively). Ten subjects (77%) received quizartinib for >1 year; 5 (38%) completed 24 cycles. Four subjects (31%) discontinued quizartinib due to adverse events. One subject (8%) experienced relapse during cycle 1 and discontinued treatment. Most common grade 3/4 adverse events were neutropenia (23%), anemia (15%), leukopenia (15%), lymphopenia (15%), and thrombocytopenia (15%). This study demonstrated acceptable tolerability and early evidence of reduced relapse rate following allo‐HCT with quizartinib maintenance compared to historical cohorts. No MTD was identified, but 60 mg daily was selected as highest dose for continuous daily administration based on randomized comparison of daily 30 and 60 mg doses in relapsed/refractory AML.

Long-Term Survival after Complete Surgical Resection and Adjuvant Immunotherapy for Distant Melanoma Metastases

BackgroundThis phase III study was undertaken to evaluate the efficacy of an allogeneic whole-cell vaccine (Canvaxin™) plus bacillus Calmette-Guerin (BCG) after complete resection of stage IV melanoma.MethodsAfter complete resection of ≤5 distant metastases, patients were randomly assigned to BCG+Canvaxin (BCG/Cv) or BCG+placebo (BCG/Pl). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and immune response measured by skin test (ClinicalTrials.gov identifier: NCT00052156).ResultsBeginning in May 1998, 496 patients were randomized. In April 2005, the Data Safety Monitoring Board recommended stopping enrollment due to a low probability of efficacy. At that time, median OS and 5-year OS rate were 38.6 months and 44.9%, respectively, for BCG/Pl versus 31.4 months and 39.6% in the BCG/Cv group (hazard ratio (HR), 1.18; pxa0=xa00.250). Follow-up was extended at several trial sites through March 2010. Median OS and 5-year and 10-year survival was 39.1 months, 43.3 and 33.3%, respectively, for BCG/Pl versus 34.9 months, 42.5 and 36.4%, in the BCG/Cv group (HR 1.053; pxa0=xa00.696). Median DFS, 5- and 10-year DFS were 7.6 months, 23.8 and 21.7%, respectively, for BCG/Pl versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG/Cv group (HR 0.882; pxa0=xa00.260). Positive DTH skin testing correlated with increased survival.DiscussionIn this, the largest study of postsurgical adjuvant therapy for stage IV melanoma reported to date, BCG/Cv did not improve outcomes over BCG/placebo. Favorable long-term survival among study patients suggests that metastasectomy should be considered for selected patients with stage IV melanoma.