Phase II Trial of Pre-irradiation KRN8602 (MX2) in Malignant Glioma Patients

KRN8602 (MX2) is a newly developed morpholino anthracycline that crosses the blood–brain barrier where it becomes distributed in brain tissue after intravenous administration. This morpholino anthracycline has been found to be effective against human glioma cells and the intracerebrally transplanted tumors in vivo.We performed a phase II trial using KRN8602 as a single agent in malignant glioma patients who had not received prior adjuvant therapy.The 13 patients (5 glioblastomas, 7 anaplastic astrocytomas and 1 malignant oligodendroglioma) enrolled received at least 1 cycle of KRN8602 at 35mg/m²/day in 3–4 week intervals by intravenous bolus. Ten of these patients could be evaluated for response, and 13 for toxicity. Three patients (1 glioblastoma and 2 anaplastic astrocytomas) demonstrated a complete response (3/10, 30%).Concerning side effects, myelosuppression was moderately severe, with 30.7% of patients developing grade 3 leukopenia. Severe nausea/vomiting was observed in 69% of the patients, however, cardiotoxicity was not observed.The results indicate that KRN8602 demonstrated modest activity against malignant glioma with relatively severe, but manageable toxicity. Further assessment of the efficacy and toxicity of KRN86O2 against malignant glioma may be worthwhile.     

A Phase II Study of KRN8602(MX2), a Novel Morpholino Anthracycline Derivative,in Patients with Recurrent Malignant Glioma

KRN8602(MX2) is a newly developed morpholino-anthracycline that has been found to cross the blood–brain barrier and be distributed in brain tissue after intravenous administration and to be effective against human glioma cells and the intracerebrally transplanted tumors in vivo. In order to confirm these promising preclinical observations clinically, we performed a phase II trial of KRN8602 in patients with recurrent malignant glioma.The 44 patients enrolled received at least 2 cycles of KRN8602 35mg/m2/day at 3–4 week intervals by intravenous bolus. Of the 44 patients, 37 could be evaluated for response, and 39 for toxicity. One patient with anaplastic astrocytoma had a complete response (1/37, 3%), and 2 patients with anaplastic astrocytoma and 1 with brain stem glioma had a partial response (3/37, 8%). The overall response rate was 11% (4/37). All patients who responded had received prior chemotherapy that included nitrosoureas. No response was observed in the patients with glioblastoma.Myelosuppression was moderately severe, with 72% of patients developing grade 3 or 4 leukopenia. Severe nausea/vomiting was observed in 31% of the patients. No severe cardiotoxicity was observed.The results indicate that KRN8602 has modest activity against recurrent malignant glioma with relatively severe, but manageable toxicity. It seems to be worthwhile to further assess the efficacy and toxicity of KRN8602 against malignant glioma, which is generally less sensitive to chemotherapy.     

Phase II study of KRN8602, 3′-deamino-3′-morpholino- 13-deoxo-10-hydroxycarminomycin hydrochloride, MX2 · HCl in patients with metastatic breast cancer

Purpose: KRN8602 (3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride, MX2 · HCl) is a newly developed anthracycline that has been found to be effective against multidrug-resistant tumor cells in vitro and in vivo. In order to clinically confirm these promising preclinical observations, we performed a phase II trial of KRN8602 in patients with anthracycline-resistant metastatic breast cancer. Methods: Of 41 patients registered with metastatic breast cancer, 37 were eligible and were given at least two cycles of KRN8602 15 mg/m² per day at 3–4 week intervals by intravenous bolus injection on days 1, 2, and 3. Results: Of the 37 patients, 6 (16.2%, with a 95% confidence interval of 4.3–28.1%) had a partial response (PR). No complete responses (CRs) were observed. The difference between response rates according to prior history of anthracycline administration was not significant. Myelosuppression was moderately severe, with grade 3 or 4 leukopenia occurring in 65%. Severe nausea/vomiting was observed in 44% of the patients. Conclusions: The results indicate that KRN8602 has modest activity in refractory metastatic breast cancer and is associated with relatively severe toxicity. Furthermore, the preclinical finding that KRN8602 overcomes anthracycline resistance was not reliably reproduced in this clinical phase II trial. Received: 20 May 1998 / Accepted: 15 October 1998     

Neoadjuvant Pyrotinib plus Trastuzumab and Chemotherapy for Stage I–III HER2‐Positive Breast Cancer: A Phase II Clinical Trial

Lessons Learned

• This is the first trial to explore the neoadjuvant therapy of pyrotinib in HER2‐positive operable and locally advanced breast cancer, in combination with epirubicin plus cyclophosphamide followed by docetaxel plus trastuzumab.
• Results primarily showed that pyrotinib in combination with epirubicin plus cyclophosphamide followed by docetaxel plus trastuzumab was effective and safe in HER2‐positive operable and locally advanced breast cancer.
• A subsequent randomized controlled trial is still warranted to confirm these results.

BackgroundThe efficacy and safety of neoadjuvant therapy of pyrotinib, a new irreversible tyrosine kinase inhibitor (TKI), was first estimated in patients with HER2‐positive breast cancer in this phase II study, in combination with trastuzumab and chemotherapy.MethodsBetween February 19, 2019, and November 20, 2019, 20 female Chinese patients with stage I–III HER2‐positive breast cancer were assigned to receive eight cycles of neoadjuvant pyrotinib (P) in combination with four cycles of epirubicin (E) and cyclophosphamide (C) followed by four cycles of docetaxel (T) and trastuzumab (H), once every 3 weeks, referred to as P + EC‐TH.ResultsA total of 19 patients completed the therapy and final surgery. The total pathological complete response (tpCR) rate was 73.7% (95% confidence interval [CI], 48.8–90.9), and no recurrence or metastasis occurred during the short‐term follow‐up period. The objective response rate (ORR) was 100% (95% CI, 82.4–100). The most common adverse events (AEs) were diarrhea and leukopenia in 18 of 20 patients (90%), but no grade 5 AEs were reported.ConclusionThis study showed that in HER2‐positive operable or locally advanced breast cancer, the tpCR rate of P + EC‐TH neoadjuvant therapy was about twice as high as that of EC‐TH neoadjuvant therapy reported in other trials, with tolerable side effects.     

Cabazitaxel Plus Lapatinib as Therapy for HER2+ Metastatic Breast Cancer With Intracranial Metastases: Results of a Dose-finding Study

Background

Lapatinib is an oral small molecule tyrosine kinase epidermal growth factor receptor-1/HER2 inhibitor that crosses the blood–brain barrier and is active against central nervous system (CNS) metastases. Cabazitaxel is a taxoid that is effective against taxane-resistant metastatic breast cancer (MBC) and has distinguished itself by its ability to cross the blood–brain barrier. The present phase II study (ClinicalTrials.gov identifier, NCT01934894) evaluated the combination of these agents to treat HER2⁺ MBC patients with CNS metastases.

Preliminary Results of a Randomized Study on Postmenopausal Women With Early Stage Breast Cancer: Adjuvant Hypofractionated Whole Breast Irradiation Versus Accelerated Partial Breast Irradiation (HYPAB Trial)

BackgroundThe purpose of this study was to report preliminary data of a randomized phase III trial comparing hypofractionated whole breast irradiation (HWBI) and accelerated partial breast irradiation (APBI) using volumetric modulated arc therapy (VMAT).Material and MethodsThe HYPAB trial enrolled postmenopausal women with biopsy-proven infiltrating breast cancer, clinically negative axilla, single T1 to T2 tumors, who were treated with breast-conserving surgery. Patients were randomized 1:1 after surgery to HWBI (40.5 Gy whole breast, 48.0 Gy to surgical bed, 15 fractions over 3 weeks) or APBI (30 Gy delivered in 5 fractions of 6 Gy given on alternate days on the surgical bed). Cosmetic outcome was the primary end point of the study.ResultsA total of 172 patients were enrolled. After a median follow-up of 36 months, 5 local failures and 3 locoregional failures were recorded, with no difference between the 2 treatment arms. Use of HWBI as compared with APBI was significantly correlated with increased incidence of overall (62% vs. 14%; P < .001) and grade 2 (18% vs. 1%; P < .001) acute skin toxicity. APBI was correlated with a lower incidence of overall late toxicity as compared with HWBI (18% vs. 41%; P = .001), but no significant difference was found in term of occurrence of grade 2 events (1% vs. 4%; P = NS). At comparative assessment between baseline and post-radiotherapy evaluation, impairment in cosmetic outcome was reported in 19 (11%) patients. Owing to premature closure of the study, no per-protocol comparison between the treatment arms was performed.ConclusionAPBI with the VMAT technique is safe and feasible, with lower acute toxicity when compared with HWBI.     

An Early Phase II Study of Etoposide (VP-16) in Advanced Gastric Cancer

An early phase II study was conducted to evaluate the anti-tumoreffects and toxicity of etoposide in patients with unresectableor relapsed advanced gastric cancer. From April 1991 to December1992, 13 patients were enrolled into this study; one was subsequentlyconsidered ineligible. Before enrollment, all the patients hadbeen treated with chemotherapy which did not include etoposide.Etoposide (100 mg/m²/day) was administered as an intravenousinfusion over 120 min for five consecutive days and was repeatedevery four weeks. Seven patients received one course of thistherapy and the remaining five received two. No patient showeda complete or a partial response. No change and progressivedisease were observed in three and nine patients, respectively.The clinical toxicities (grade 3–4; WHO) of leukocytopenia,anemia and alopecia occurred in 50, 42, and 42% of the patients,respectively. We conclude that this dose of etoposide administeredaccording to the present schedule is ineffective in previouslytreated patients with advanced gastric cancer.     

A Randomized Phase II Trial Investigating the Effect of Platelet Function Inhibition on Circulating Tumor Cells in Patients With Metastatic Breast Cancer

BackgroundBlockade of platelet activation and aggregation can inhibit metastasis in preclinical models and is associated with cancer prevention. To test whether disruption of platelet function with clopidogrel and aspirin would decrease the number of circulating tumor cells (CTCs) in patients with metastatic breast cancer, a randomized phase II study was performed.MethodsPatients with metastatic breast cancer who were not currently receiving cytotoxic chemotherapy were eligible. Patients were randomized to receive either clopidogrel and aspirin or to a control group receiving no treatment. Phlebotomy was performed at baseline, at 2 and 4 weeks, and monthly thereafter to obtain specimens to assess CTC, platelet aggregation, and thrombin activity. The primary end point was the proportion of patients with detectable CTCs at 1 month.ResultsForty-eight patients were enrolled and 42 were evaluable at 1 month. Baseline CTC numbers were ≥ 5 in 13% and ≥ 1 in 65% of patients. Despite adequate platelet function inhibition in the treatment group, the proportion of patients with detectable CTCs was similar between the clopidogrel/aspirin and control groups at baseline (P = .21) and 4 weeks (P = .75), showing no treatment effect. Measured endogenous thrombin potential did not correlate with CTC number. No bleeding-related serious adverse events (SAEs) occurred.ConclusionThe baseline CTC numbers were lower than expected, decreasing the ability to detect an impact of platelet inhibition on CTCs. Clopidogrel and aspirin were well tolerated. Future studies evaluating the potential therapeutic role of antiplatelet therapy in breast cancer remain of interest, and they may be informed by these results.     

Phase II trial of daily oral perillyl alcohol (NSC 641066) in treatment-refractory metastatic breast cancer

Purpose Perillyl alcohol (POH) is a naturally occurring lipid with preclinical activity against mammary carcinomas. We conducted a phase II multi-institutional study of oral POH administered four times daily in women with advanced treatment-refractory breast cancer. Methods Eligible women were treated with POH four times daily at 1,200–1,500 mg m⁻² dose⁻¹ on a 28-day cycle. Patients tolerating 1,200 mg m⁻² day⁻¹ four times daily after one cycle were dose-escalated to 1,500 mg/m². The primary endpoint was 1-year freedom-from-progression (FFP) rate. Secondary endpoints were response rate, tolerability and correlative evaluations. Results Twenty-nine cycles of POH were administered to 14 women. Three patients were dose-escalated to 1,500 mg/m². Grade 1 and grade 2 gastrointestinal effects and fatigue were predominant toxicities. Of seven patients receiving up to one cycle, three stopped therapy due to intolerance. Only two patients received more than two cycles, with disease stabilization of 3 and 8 months. Thirteen patients were evaluable for response. One-year FFP rate was zero. No objective responses were seen. The median time to progression was 35 days (95% CI, 29–123 days). Median overall survival was 389 days (95% CI, 202–776 days). Pharmacokinetic parameters were similar to previous investigations. The ability to correlate plasma TGF-β1 levels with outcome was limited by lack of clinical benefit and inter- and intra-patient variability. Conclusions Enrollment was suspended short of planned accrual because of lack of response and poor tolerance to POH. This regimen does not appear to provide benefit in advanced treatment-refractory breast carcinoma.     

Sorafenib Plus Irinotecan Combination in Patients With RAS-mutated Metastatic Colorectal Cancer Refractory To Standard Combined Chemotherapies: A Multicenter,Randomized Phase 2 Trial (NEXIRI-2/PRODIGE 27)

BackgroundNo treatment option was available for patients with RAS-mutated (RASmt) metastatic colorectal cancer (mCRC) who progress after standard combined chemotherapies at the time of the study. After promising results in phase II, the aim of the present NEXIRI-2/PRODIGE 27 trial was to assess the 2-month non-progression rate for sorafenib (NEX) plus irinotecan (IRI), that is, NEXIRI, treatment.MethodsPatients with RASmt mCRC after failure of oxaliplatin, IRI, fluoropyrimidines, and bevacizumab were randomized between NEXIRI (IRI 120-180 mg/m² intravenous, D1 = D15 plus oral NEX 400 mg twice a day) versus IRI (180 mg/m²) versus NEX. Primary endpoint was the 2-month non-progression rate. Secondary endpoints included progression-free and overall survival (PFS and OS), safety, and germline cyclin D1 (CCND1) rs9344 polymorphisms analyses.ResultsA total of 173 patients were included, 59 in NEXIRI, 57 in IRI, and 57 in NEX arms. The 2-month non-progression rate was 52.6% (95% confidence interval [CI]: 39%–66%), 21.4% (10%–33%), and 19.3% (9%–30%) for NEXIRI, IRI, and NEX. Median PFS was 3.6 (95% CI: 2–4.2), 1.7 (1.7–1.8), and 2 (1.8–2.3) months and the median OS was 7.2 (5.8–9.4), 6.3 (4.8–8), and 5.6 (3.9–7.7) months for NEXIRI, IRI, and NEX, respectively. For NEXIRI rs9344CCND1 A/A genotype patients, OS was 19.6 months (95% CI: 4.8–not reached). Main grade 3 toxicities included neutropenia, febrile neutropenia, diarrhea, hand-foot syndrome, and hypertension.ConclusionsIn patients with RASmt mCRC who progressed after standard combined chemotherapies, the results of 2-month non-progression rate and median PFS in the NEXIRI arm were in favor of an increase of the time before progression.     

Impact of Granulocyte Colony-Stimulating Factor (G-CSF) and Epoetin (EPO) on Hematologic Toxicities and Quality of Life in Patients During Adjuvant Chemotherapy in Early Breast Cancer: Results From the Multi-Center Randomized ADEBAR Trial

BackgroundHematologic toxicities are one of the greatest challenges in adjuvant chemotherapy for breast cancer. This analysis of the ADEBAR trial aims to evaluate application and effect of granulocyte colony-stimulating factor (G-CSF) and epoetin alfa (EPO) on hematologic parameters and fatigue in patients with breast cancer during chemotherapy.Patients and MethodsIn the ADEBAR trial, 1493 patients with node-positive primary breast cancer were randomized to either 6 × 5-fluorouracil, epirubicin, and cyclophosphamide (FEC120) or 4 × epirubicin and cyclophosphamide followed by 4 × docetaxel (EC-DOC). Co-medication with G-CSF or EPO was applied to treat chemotherapy-induced leukopenia or anemia. Fatigue was assessed at baseline and after one-half of the chemotherapy.ResultsIn total, 899 patients could be included in the analysis. There was no evidence for an association between leucocyte or hemoglobin levels and application of G-CSF and EPO in the preceding cycle, respectively. Hemoglobin levels (B = −0.41; P < .001) were affected by treatment regimen. Fatigue during chemotherapy was mostly affected by the level of fatigue before the start of chemotherapy (B = 0.41; P < .001). Patients with G-CSF application in the preceding cycle showed an increased fatigue score (B = 5.43; P = .02).ConclusionWe showed that fatigue during adjuvant chemotherapy was mostly affected by the level of fatigue present before the start of chemotherapy. This result suggests that the level of fatigue before the start of treatment should be included as an important factor when deciding on type and toxicity of chemotherapy in early breast cancer.     

Phase 2 Study of Weekly Paclitaxel Plus Estramustine in Metastatic Hormone-Refractory Prostate Carcinoma: ECOG-ACRIN Cancer Research Group (E1898) Trial

Introduction

This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC).

Randomized Phase II Study of Two Doses of Pixantrone in Patients with Metastatic Breast Cancer (NCCTG N1031, Alliance)

BackgroundAnthracycline use in metastatic breast cancer (MBC) is hindered by cumulative exposure limits and risk of cardiotoxicity. Pixantrone, a novel aza-anthracenedione with structural similarities to mitoxantrone and anthracyclines, is theorized to exhibit less cardiotoxicity, mainly due to lack of iron binding. We conducted a randomized phase II study to evaluate the efficacy and safety of 2 dosing schedules of pixantrone in patients with refractory HER2-negative MBC.MethodsIntravenous pixantrone was administered at 180 mg/m² every 3 weeks (group A) versus 85 mg/m² on days 1, 8, and 15 of a 28-day cycle (group B). Primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS), median 6-month PFS, overall survival (OS), safety, quality of life, and serial assessment of circulating tumor cells. A 20% ORR was targeted as sufficient for further testing of pixantrone in this patient population.ResultsForty-five patients were evaluable, with 2 confirmed partial responses in group A and 1 in group B. The trial was terminated due to insufficient activity. Overall median PFS and OS were 2.8 (95% confidence interval [CI]: 2.0-4.1) and 16.8 (95% CI: 8.9-21.6) months, respectively. Notable overall grade 3-4 adverse events were the following: neutrophil count decrease (62%), fatigue (16%), and decrease in ejection fraction (EF) (4%).ConclusionPixantrone has insufficient activity in the second- and third-line MBC setting. It appears, however, to have limited cardiotoxicity. (ClinicalTrials.gov ID: {"type":"clinical-trial","attrs":{"text":"NCT01086605","term_id":"NCT01086605"}}NCT01086605).