Bevacizumab for the treatment of brain radionecrosis in cancer patients.

e19352 Background: Brain radionecrosis (BRN) occurs as a result of radiation therapy for brain tumors or metastatic brain lesions. BRN is characterized by an increase in permeability and disruption of the blood-brain barrier (BBB). There are currently no standard treatment options for BRN. While the mechanism of BRN is unknown, it is hypothesized that there is an inflammatory reaction of the local tissue to radiation which results in a continuous process involving endothelial cell dysfunction. This leads to tissue hypoxia and increased vascular endothelial growth factor (VEGF) which in turn causes capillary leakage, progressive BBB dysfunction, and cerebral edema. Bevacizumab (BEV), a humanized monoclonal antibody with action against VEGF, has recently been used in some studies for the treatment BRN. BEV essentially blocks VEGF from reaching its targets on the endothelium, thus making it an ideal treatment modality for BRN. Methods: The primary purpose of this study is to assess the effectiveness and safety of BEV for the treatment of BRN. Fifteen patients (pts), 14 diagnosed with lung cancer and one with breast cancer, that had BRN and treated with BEV between January 2014 and November 2019 were identified from Memorial Cancer Institute's database. A retrospective chart review analyzing pts's age, sex, BEV dose, dosing frequency, number of treatments received, medication-related adverse effects, and clinical benefit was conducted. Brain imaging pre-treatment and after four cycles of therapy were compared to assess the efficacy of BEV. Pts who exhibited clinical benefit (complete response (CR), partial response (PR), or stable disease (SD)) received an additional four cycles of treatment. Results: The median age was 65 years (y) (49-78y) and 10/15 (67%) of pts were female. Clinical benefit was achieved in 13/15 (87%) of pts. The most frequent dosing regimen administered was 10 mg/kg every two weeks and the median number of cycles given was eight cycles (1-12). Treatment with BEV was well tolerated with eight pts (53%) experiencing BEV-related Grade 2 or less adverse effects (AE), including hypertension (27%), proteinuria (13%), thrombocytopenia (7%), and mild nose bleeds (7%). There were no Grades 3-5 AE. Conclusions: This study demonstrates that there is a clinical benefit when administering BEV for the treatment of BRN. BEV was well tolerated and has an acceptable safety profile.

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Phase II trial assessing niraparib with or without dostarlimab (anti-PD-1) in recurrent endometrial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5574 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5574-5574

Author(s):

Ainhoa Madariaga ◽

Swati Garg ◽

Nairi Tchrakian ◽

Neesha C. Dhani ◽

Waldo Jimenez ◽

...

Keyword(s):

Endometrial Carcinoma ◽

Phase Ii ◽

Clinical Benefit ◽

Phase Ii Trial ◽

Treatment Options ◽

Single Agent ◽

Median Number ◽

Toxicity Assessment ◽

Clinical Benefit Rate ◽

Number Of Cycles

5574 Background: Treatment options in recurrent endometrial carcinoma (EC) are limited. Endometrioid EC shows alterations in PTEN, a possible biomarker of response to PARP inhibitors (PARPi). Similarly, homologous recombination deficiency (HRd), a biomarker of response to PARPi in ovarian cancer, is associated with serous EC harbouring TP53 mutations. Preclinical EC models have shown synergy between combining a PARPi and immune checkpoint inhibitor (ICI). Methods: A pilot multi-centre, non-randomized, phase II trial enrolled patients (pts) with recurrent serous or endometrioid EC in two consecutive cohorts (NCT03016338). In the first cohort (C1) pts received niraparib 200 or 300 mg qd, based on baseline body weight and platelet count, in 4 week (w) cycles. In the second cohort (C2) niraparib was given with dostarlimab 500 mg q 3 w for 4 cycles, followed by 1000 mg q 6 w thereafter. There was no limit on prior lines of therapy. Prior ICI was not allowed in C2. Primary endpoint was clinical benefit rate (CBR; complete, partial response or stable disease ≥16w). Secondary endpoints included toxicity assessment and ORR. CT scans were performed q 8 w. Potential biomarkers were assessed in archival tissue by IHC (PTEN, p53, MMR, PDL-1 [threshold 1%]) and a NGS panel (including TP53, PTEN, POLE and other HRd genes). Tumour mutational burden-high (TMBh) was defined as top 20% mutation load. Results: In C1, 25 pts were enrolled (23 evaluable for response). Median age was 69 years old, 64% had serous EC, 72% were platinum resistant (PlatR) and median prior therapies was 2 (range 1-4). Median number of cycles was 3. The CBR was 20% (95% CI: 9-39) and median clinical benefit (CB) duration was 5.3 (1.8-7.2) months. The ORR was 1/23 (4%; 0-20). Related grade (g) ≥3 AEs ≥10% were anemia (24%), fatigue (16%) and thrombocytopenia (16%). In C2, 22 pts were enrolled (all evaluable) and two continue on-treatment. Median age was 64 years old, 46% had serous EC, 68% were PlatR and median prior therapies was 2 (1-6). Three pts had MMR deficient (MMRd) tumors (14%) and one pt a POLE mutation (5%). Median number of cycles was 3. The CBR was 31.8% (16-53) and median CB duration was 6.8 months (3.7-9.5). The ORR was 3/22 (14%; 3-35), out of the three responders one had MMRd and one a POLE mutation. Related g≥3 AEs ≥10% were anemia (27%) and neutropenia (14%). No significant correlation was detected between CB and IHC markers (PTEN, p53, MMR, PDL-1), or NGS ( PTEN, TP53, HRd TMBh) in C1 and C2. Conclusions: Niraparib as single agent for treatment in a PlatR enriched recurrent EC population showed modest activity with clinical benefit rate at 16w of 20%. The combination of niraparib and dostarlimab showed a clinical benefit rate at 16w of 31.8% in a predominantly PlatR recurrent EC. PTEN loss by IHC or NGS, and alterations in HRd genes did not correlate with clinical benefit. Clinical trial information: NCT03016338.

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Effect of lenalidomide (LEN) on biochemical responses and clinical benefit (CB) as a single agent in chemotherapy-naive castration-resistant prostate cancer (CRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.128 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 128-128 ◽

Cited By ~ 1

Author(s):

Chadi Nabhan ◽

Anand Patel ◽

Dana Villines ◽

Kathy Tolzien ◽

Susan K. Kelby ◽

...

Keyword(s):

Adverse Events ◽

Clinical Benefit ◽

Single Agent ◽

Complete Response ◽

Median Number ◽

Castration Resistant Prostate Cancer ◽

Serious Adverse Events ◽

Biochemical Responses ◽

Grade 3 ◽

Dose Reductions

128 Background: LEN has anti-angiogenesis and immunomodulatory properties making it ideal to investigate in CRPC. We report on a phase II study investigating LEN in chemotherapy-naïve CRPC patients (pts) Methods: Eligible pts received LEN at 25 mg daily on days 1 – 21 every 28-days until progression. Daily aspirin or coumadin were required. Responses were assessed every 2 cycles. Toxicity was assessed every cycle. Primary end point: The CB of LEN [Sum of complete response (CR), partial response (PR) and stable disease (SD)]. Secondary end points: Toxicity, time to radiographic and PSA progression (TTP and TTP-PSA), time to next treatment (TTNT), overall survival (OS), and LEN’s impact on quality of life (QOL). Results: 31 pts were enrolled; 27 response-evaluable (1 withdrew consent, 3 off per choice after adverse events). Median age is 74 (range 58-89) with 24 (77%) having Gleason ≥ 7 disease. Median PSA is 66 (2.1-918.6). Six pts (19%) had liver/lung involvement. Fourteen pts (51%) showed biochemical response with 4 (15%) having >50% PSA drop. TTP-PSA is 4 months (2-11). No radiographic responses seen but 17 pts had SD for a median of 4 months (2-16) (CB=55%). Median number of LEN cycles was 3 (2-15). With a median follow-up of 18 months (5-38), 17 patients (55%) remain alive; median OS of 18 months. Grade 3/4 hematologic toxicities were most common (neutropenia 41%, leukopenia 12%, anemia 9%, thrombocytopenia 9%). Other grade 3/4 toxicities: venothromboembolism, atrial fibrillation, and dehydration (6% each). Serious adverse events (SAEs) were witnessed in 10 pts (32%) with only 1 (3%, rash) definitely related to LEN. Others were not related or possibly related. Of 27 pts, 7 (26%) had a dose reduction and 2 (7%) required two dose reductions. Dose reductions occurred after cycle 3. QOL scales suggested no adverse impact. Median TTNT is 2 months (9 pts received chemotherapy, 10 pts went onto studies, 3 pts received hormonal therapies, 4 pts received radiation, 3 pts had no therapy yet, and 2 pts remain on LEN). Conclusions: LEN is active as monotherapy in CRPC. Biochemical responses are witnessed and clinical benefit is observed. Myelosuppression is the most common toxicity.

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Neoadjuvant chemotherapy for locally advanced cervical cancer: Experience at the Instituto Oncologico Nacional SOLCA Guayaquil.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e15571 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e15571-e15571

Author(s):

Guillermo Paulson ◽

Katherine Garcia ◽

Mayra Santacruz ◽

Ruth Ginger Engracia ◽

Jose Francisco Mendoza

Keyword(s):

Cervical Cancer ◽

Neoadjuvant Chemotherapy ◽

Invasive Cervical Cancer ◽

Locally Advanced ◽

Progression Free Survival ◽

Complete Response ◽

Median Number ◽

Number Of Cycles ◽

Clinical Records ◽

Cancer Experience

e15571 Background: Cervical cancer is the most common malignancy of women in Ecuador. The main problem of concomitant chemo-radiotherapy (CRT) is the delay in starting radiation therapy, economic and logistical problems for high demand in radiotherapy. It has been neoadjuvant chemotherapy (NACT) followed by CRT the main treatment at our center in order to find an alternative to long waits before the start of radiotherapy. The aim of this study was to determine the response to NACT followed by CRT in terms progression-free survival (PFS) and overall survival (OS). Methods: diagnosed with invasive cervical cancer locally advanced stage II-III were analyzed retrospectively reviewed clinical records of pre-existing data from 2008 to 2010. Results: after meeting the criteria of exclusion, leaving 116 cases. The median age: 49 years (range: 28-82 years). The histology was 73% (85) squamous cell carcinoma, 26% (30) adenocarcinoma and 0.9% (1) not specified. Patients with stage IIB: 81.9% (95), IIIA: 10.3% (12), IIIB: 7.8% (9). Of the 116 patients 69% (80) received NACT. The main NACT was paclitaxel 175mg/m2 + Cisplatin 75mg/m2 every 3 weeks 63.8% (74), the remaining group received another protocol, the median number of cycles of NACT was 5 (1 - 8 cycles), the start of radiotherapy since the conclusion of NACT was 53 days on average (1 to 285 days) and the main regimen of CRT concomitant was cisplatin 40mg/m2 weekly 47.5% (38). In the 49 patients who underwent NACT followed by CRT, a radiological study showed, complete response (CR) 38.8% (19), 18.4% partial response (PR) (9), disease progression (DP) 12.2% (6), stable disease (SD) 8.2% (4) and the end of treatment evaluation gynecological was performed and CR was obtained in 59.2% (29). Persistent or progressive disease after treatment was 22.4% (11), recurrence was 12.2% (6), local recurrence 2.0% (1), distant metastasis 10.2% (5). OS of NACT followed by CRT was 93.9% (46) and PFS was 65.3% (32), OS after CR was 96% (25 / 1) and then 91.7% PR (24 / 2) with p: 0.439. Conclusions: NACT followed by CRT is a valid option because it improves disease-related symptoms, but OS did not improve significantly even after CR.

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A non-randomized phase II study of sequential irinotecan (CPT) and flavopiridol (F) in patients (pts) with advanced hepatocellular carcinoma (HCC)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4148 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4148-4148 ◽

Cited By ~ 2

Author(s):

G. K. Abou-Alfa ◽

R. D. Carvajal ◽

K. Y. Chung ◽

R. A. Ghossein ◽

M. Capanu ◽

...

Keyword(s):

Phase I ◽

Median Number ◽

Advanced Hepatocellular Carcinoma ◽

Wild Type ◽

Advanced Hcc ◽

Progression Of Disease ◽

Wild Type P53 ◽

Pre Treatment ◽

Number Of Cycles ◽

Induced Apoptosis

4148 Background: F is a CDK inhibitor which potentiates CPT- induced apoptosis. In a phase I trial of CPT 100mg/m2 followed 7 hours later by F given over 1 hour weekly for 4 out of 6 weeks (Shah, Clin Can Res 2005), 2 pts with advanced HCC had stable disease (SD) for 14+ months. In the same phase I study, patients who were p53 wild-type (negative p53 staining), and whose p21 remained stable or was non-detectable on the post-treatment biopsy, were noted to have SD or a partial response. Methods: Pts with advanced HCC, no prior systemic therapy, Child’s-Pugh score A, B7 or B8, and KPS ≥ 70%, received 100 mg/m2 of CPT, followed 7 hours later by 60 mg/m2 of F over 1 hour weekly for 4 out of 6 weeks. The trial had a two stage design, with a planned accrual of 30 pts. The primary endpoint was TTP. Tumor response was assessed every 2 cycles using revised WHO criteria. p53 immuno-staining was performed on pre-treatment paraffin preserved tissues. A cut-off of 20% defined positive mutant versus negative wild-type p53 status. Results: 16 pts were enrolled: median age 64 (range 26–84), KPS 80% (70–90%), and 10 males/6 females. 13 pts received therapy, two progressed before starting, and one patient (pt) was excluded because pathology re-review did not confirm HCC. 1 pt was excluded because of consent withdrawal after first dose of therapy. This pt was included in the toxicity analysis. The median number of cycles given was 2 (range 1–8 cycles). Grade 3 and 4 toxicities included dehydration (4: 30%) diarrhea (2: 15%) febrile neutropenia (6: 46% - 4 events in one pt) and fatigue/weakness (3: 23%). Therapy had to be discontinued in 2 pts because of toxicity. TTP was 2.6 months (95% CI 2.43–8.42). One patient had SD for over a year, 8 had progression of disease (POD), and 4 came off study because of toxicity. Mutational p53 was evaluated in 7 pts. The pt with SD had wild type p53. Three pts with POD had mutant p53, while the other 3 had wild type 53. Conclusions: CPT followed by F is an ineffective therapy for HCC. This therapy was relatively poorly tolerated, likely contributed to by underlying cirrhosis in HCC, but similar to our experience of CPT in HCC. While p21 level pre and post therapy is lacking, the wild type p53 of the patient with SD maybe a predictor of response in HCC where p53 mutations are common. No significant financial relationships to disclose.

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Randomized phase II/III clinical trial of induction chemotherapy (ICT) with either cisplatin/5-fluorouracil (PF) or docetaxel/cisplatin/5-fluorouracil (TPF) followed by chemoradiotherapy (CRT) vs. crt alone for patients (pts) with unresectable locally advanced head and neck cancer (LAHNC)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.5515 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 5515-5515 ◽

Cited By ~ 17

Author(s):

R. Hitt ◽

J. Grau ◽

A. Lopez-Pousa ◽

A. Berrocal ◽

C. García-Giron ◽

...

Keyword(s):

Clinical Trial ◽

Induction Chemotherapy ◽

Response Rate ◽

Locally Advanced ◽

Complete Response ◽

Median Number ◽

Time To Progression ◽

Primary Tumor Site ◽

N Stage ◽

Number Of Cycles

5515 Background: we have previously reported that ICT plus CRT is more active than CRT alone in pts with unresectable LAHNC (Hitt et al: ASCO 2005, abstract 5578). Here we present new data of efficacy and time to progression (TTP) in this trial. Methods: Patients: eligible pts included those with unresectable LAHNC, measurable disease, adequate organ function and ECOG 0–1. Pts were stratified according to primary tumor site. Treatment: Induction chemotherapy regimens (3 cycles): PF : P 100 mg/m2 day (d) 1, then F 1000 mg/m2 c.i. d1–5 q 21d; TPF: T 75 mg/m2 d1, P 75 mg/m2 d1, F 750 mg/m2 c.i. d 1–5 q 21 d plus G-CSF and ciprofloxacin. Chemoradiotherapy: conventional RT up to 70 Gy plus P 100 mg/m2 d 1–22–43 Results: Patients: a total of 310 pts have been accrued. Pts/tumor characteristics (ECOG, age, primary site, T/N stage) were well balanced among the three arms. T/N stage: T3–4 (88%); N2–3 (63%); pharynx-oropharynx site (62%). Treatment: Median number of cycles of ICT: 3; median dose of RT: 70 Gy, median number of cycles of P during RT in three arms: 3. Efficacy: Complete Response: 70% (ICT + CRT) vs. 49% (CRT alone) (p = 0.01). The response rate was similar between TPF and PF. Time to progression (TTP) in months: 16 (TPF + CRT); 12 (PF + CRT) vs 8 (CRT alone) (log-Rank= 0.02). G 3/4 toxicity (NCI criteria): Febrile neutropenia: 21% (TPF); mucositis: 10% (PF). Mucositis was observed in 55% (TPF + CRT), 60% (PF + CRT) and 36% (CRT alone) of the pts, respectively Conclusions: The results of the present randomised clinical trial demonstrate that the combination of ICT + CRT significantly increases the complete response rate and prolongs TTP when compared to CRT alone in patients with unresectable LAHNC. No significant financial relationships to disclose.

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GEMOX as first-line chemotherapy in advanced pancreatic cancer (APC): A monoinstitutional experience

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.15179 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 15179-15179

Author(s):

M. Di Marco ◽

E. Nobili ◽

R. Di Cicilia ◽

G. Brandi ◽

S. Bertolini ◽

...

Keyword(s):

Advanced Pancreatic Cancer ◽

Complete Response ◽

Median Number ◽

Phase Iii ◽

First Line ◽

Kaplan Meier ◽

Phase Iii Trials ◽

Number Of Cycles ◽

The Impact ◽

Line Chemotherapy

15179 Background: To date, gemcitabine (GEM) remains the cornerstone of chemotherapy (CHT) for APC. According to GERCOR and GISCAD phase III trials the combination of GEM and oxaliplatin (GEMOX) has proven superior to GEM alone in terms of response rate (RR), time to progression (TTP) and clinical benefit rate (CBR). Methods: We conducted a retrospective analysis on 19 patients (pts) affected with histologically-confirmed APC, in order to determine the impact of GEMOX as first-line chemotherapy in terms of objective responses (OR) and TTP, using the Kaplan-Meier method. Among the 19 pts considered there were 15 males and 4 females (median age at diagnosis of 60.84 yrs; ECOG 0–2). The staging, according to AJCC criteria, was: IIB in 1 case, III in 5 cases and IV in the 13 remaning cases. The only metastatic site was the liver (in 13/19 pts). Ten of the 19 pts underwent surgical treatment prior to CHT: 2 radically resected (R0) subsequently treated with GEMOX after recurrence, 4 with positive margins (R1) and 4 surgically palliated. All pts received GEM 1000 mg/m2/d1 + oxaliplatin 100 mg/m2/d2 every 2 weeks. The median number of cycles was 5.89. Results: Among the 19 pts, 3 had a partial response (PR, 15.69%), 6 had stable disease (SD, 31.57%); no complete response was observed and 10 pts had progressive disease (PD, 52.63%). The overall disease control rate (DCR: PR + SD) was 47.37% while the OR were 15.69%. The median survival observed was 9.03 months (95% C.I. 5.15–12.91) and the median TTP was 6.13 months (95% C.I. 2.81–9.46). The main toxicities were: leucopenia, piastrinopenia, diarrhoea, nausea, fever and peripheral neuropathy; 3 pts discontinued the treatment due to grade 3–4 neurotoxicity. Conclusions: In our experience GEMOX gives an improved control of APC in terms of OR and TTP, with acceptable toxicity. The OS is in accordance to literature as well as the other data. No significant financial relationships to disclose.

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Effect of sorafenib on chemotherapy resistance and refractoriness in castration-resistant prostate cancer (CRPC)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e16105 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e16105-e16105

Author(s):

C. Nabhan ◽

K. Tolzien ◽

T. M. Lestingi ◽

A. Galvez ◽

J. D. Bitran

Keyword(s):

Clinical Benefit ◽

Kinase Inhibitor ◽

Chemotherapy Resistance ◽

Complete Response ◽

Median Number ◽

Castration Resistant Prostate Cancer ◽

Chemotherapy Agent ◽

Hand Foot Syndrome ◽

Psa Response ◽

Grade 3

e16105 Background: There is no standard for CRPC once chemotherapy fails. In studies employing docetaxel (D), 35–39% of pts did not complete therapy due to progression and only 45–50% had a PSA response. This implies that many pts develop resistance to D. Sorafenib is a multi kinase inhibitor with antiangiogenesis properties. We hypothesized that sorafenib could overcome chemotherapy resistance in these pts. Methods: Eligible pts must have progressed while on either D or mitoxantrone (M). They received sorafenib at 400 mg orally twice/daily in addition to the chemotherapy agent they were on. Sorefinib/chemotherapy combination was given for a maximum of 6 cycles followed by sorafenib monotherapy until progression. Primary end point was safety of the sorafenib/chemotherapy combination. Secondary end points included the overall clinical benefit calculated as the sum of complete response (CR), partial response (PR), and stable disease (SD), toxicity, and time to disease progression (TTP). Results: To date, 15 pts have been enrolled; 14 are evaluable. Eleven pts were on D and 4 on M. Median age was 68 (range 61–83), median PSA was 111.2 ng/ml (13.6–1703.9). Nine pts (60%) had visceral and bone disease. Median PSA-DT pre-study was 2 months (0.5–6) and median time from last chemotherapy to starting study was 4 weeks. Median number of given cycles was 6.5 (2–12). Six pts did not require dose reduction, 2 others were re-escalated to the full dose. Sorafenib was safely combined with chemotherapy with 6 pts experiencing grade 3 fatigue, 3 developing grade 3 hand/foot syndrome, and 1 experiening grade 3 diarrhea. Eleven pts (73%) had SD radiographically that lasted a median of 6.7 months. In all, 6 out of 14 pts (42%) had a PSA decline after adding sorafenib and 3 (21%) had stable PSA. Of these 9 pts (PR+SD), 2 never doubled their PSA. Two pts had PSA decline after withdrawing sorafenib. Median TTP for PSA was 3.75 months. PSA responses did not correlate with radiographic changes or clinical benefit. With a median follow-up of 8 months, 5 pts (33%) remain alive with 1 continuing on therapy without progression. Conclusions: Sorafenib overcomes chemotherapy-refractoriness and failures in CRPC. [Table: see text]

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Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies in the Treatment of Patients With Concussion

Neurology ◽

10.1212/01.wnl.0000801812.93958.f8 ◽

2021 ◽

Vol 98 (1 Supplement 1) ◽

pp. S9.1-S9

Author(s):

Jennifer McVige ◽

Megan Rooney ◽

Dylan Lis

Keyword(s):

Monoclonal Antibodies ◽

Adverse Effects ◽

Retrospective Chart Review ◽

Calcitonin Gene Related Peptide ◽

Mean Difference ◽

Related Peptide ◽

Headache Severity ◽

Calcitonin Gene ◽

Response Switching ◽

Pre Treatment

ObjectiveInvestigate the efficacy of 3 anti-Calcitonin Gene-Related Peptide monoclonal antibodies (anti-CGRP mAbs), fremanezumab, galcanezumab, and erenumab, in concussion patients with post-traumatic headache (PTH) with a migraine phenotype.BackgroundA study using monoclonal antibodies in mice with mild traumatic brain injury saw improvements in cutaneous allodynia.1 A study from Denmark using erenumab for PTH found patients had an 82% decrease in the number of headache days. This study also demonstrated that 44% of patients had a reduction in HIT-6 score = 5 after 9–12 weeks of treatment.2.Design/MethodsRetrospective chart review of patients diagnosed with PTH (n = 168) evaluated HIT-6, number of reported headache days, and the number of modifiable concussion variables (headache, dizziness, attention/concentration deficit, mood and sleep disturbance) prior to initiation of anti-CGRP mAbs and after at least 3 months of treatment were recorded.ResultsPatients saw a decrease in HIT-6 score (p < 0.0001), with a mean difference of −4.26 from pre-treatment to at least 3 months after treatment. When evaluating 5 concussion symptom categories, patients experienced x¯ = 2.35 symptoms prior to anti-CGRP mAbs treatment, and x¯ = 1.67 after at least 3 months of treatment. Patients also experienced a decrease in the number of headache days per month (<0.0001) with a mean difference of −7.25 (range 0–30) headache days per month. Seven patients experienced adverse effects (1 patient had 2 different adverse effects), including injection site rash, fatigue, constipation, and dizziness. Only one patient discontinued medication due to adverse event.ConclusionsAnti-CGRP mAbs used to treat PTH showed improved headache severity and frequency, as well as a decreased number of overall concussion symptoms. There was a subset of patients with a more robust response. Switching anti-CGRP mAbs was beneficial in some patients.

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Phase II Trial of Oblimersen Sodium (G3139), Dexamethasone (Dex) and Thalidomide (Thal) in Relapsed Multiple Myeloma Patients (Pts).

Blood ◽

10.1182/blood.v104.11.2400.2400 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2400-2400

Author(s):

Ashrof Z. Badros ◽

Olga Goloubeva ◽

Bashi Ratterree ◽

Sabrina Natt ◽

Aaron Rapoport ◽

...

Keyword(s):

Gene Expression ◽

Median Duration ◽

Median Number ◽

Mitochondrial Pathway ◽

Pcr Analysis ◽

Protein Levels ◽

Duration Of Response ◽

Clinical Responses ◽

Pre Treatment ◽

Number Of Cycles

Abstract Bcl-2 acts as an important regulator of the mitochondrial pathway of apoptosis and promotes resistance of MM cells to chemotherapy. The Bcl-2 antisense oligonucleotide G3139 specifically targets Bcl-2 and may enhance the anti-tumor efficacy of Dex and Thal. In this trial G3139 was administered at 5 mg to the first 3 Pts and then 7 mg/kg/d by IVCI for 7d of 21d cycle. On day 4, Pts started Dex 40 mg daily for 4 d and Thal 100-400 mg as tolerated. After 3 cycles, responding Pts continued G3139 on a 5-week cycle with Dex 20 mg x 4d and Thal at the tolerated daily dose for up to 1 yr with an optional second yr for responding Pts. Thirty-three Pts treated to date had the following characteristics: median age 60 yrs (range: 28- 76), 22 males; 16 Pts had complex karyotypes; 14 Pts had B2M > 2.5 g/dl; LDH >1.5 normal in 7 Pts; Cr >1.5 mg/dl in 6 Pts; platelets <100,000/ul in 4 Pts. Pts had received a median of 3 prior regimens (range 2-4) including auto-SCT. Seventeen Pts had received prior Thal for a median duration of 6.5 mos. (range 2–8); 11 had no response or progressed on Thal. G3139/Thal/Dex regimen was well tolerated. The median number of cycles per Pt was 8 (range: 1–16). Toxicities included reversible increase in Cr from a median of 1.2 (0.6–2.5) at baseline to 1.5 (range: 0.9–2) at cycle 6. G3139 dose was decreased (3–5 mg/kg/d) for Cr elevations in teh majority of Pts. Thrombocytopenia <100K occurred between cycle 1 and 2 (P= 0.008), and was reversible. Other toxicities (>grade 2) included fatigue, neutropenia, fever, electrolyte disturbance, muscle cramps, rash, hypotension, constipation and infections. Only 3 Pts maintained 400 mg/d of Thal, most Pts required dose reduction to 50–200 mg/d due neuropathy. Thirty Pts were evaluable for response; 24 Pts (80%) had documented responses, including 2 CR, 4 near-CR (+ immunofixation) and 12 PR; 6 had minimal response and 6 Pts had PD. The median duration of response is 13 mos. The estimated PFS is 12 mos and the median OS is 17.4 mo. The upper limits of the 95% confidence interval for PFS and OS have not been reached. At a median follow up of 1 yr (range 1.5–16.6 mo), 7 Pts had died and 26 are alive, of them 16 Pts continue on the study. Responding Pts had an early and significant increase in polyclonal IgM from a median baseline of 35.5 mg/dl (range: 8–75) to 94 (45–211) after cycle 3 (P=0.005), suggesting activation of the innate immune system. CD138+ cells were isolated from BM aspirates pre-treatment, and on d 4 or 7, and 28. Western blot analysis of Bcl-2 protein demonstrated demonstrated a decrease in Bcl-2 levels after normalization for protein loading by densitometry in 3 of 7 Pts with sufficient cells for analysis. The change of Bcl-2 protein levels did not correlate with response. Real time quantitative RT-PCR analysis was subsequently used to evaluate changes in Bcl-2 gene expression. Of 9 Pts evaluated, 6 demonstrated a significant decrease in Bcl-2 mRNA expression when normalized against GAPDH; 5 of them had a clinical response. In conclusion, G3139, Dex and Thal regimen is well tolerated in relapsed MM Pts. G3139 was associated with significant decrease in Bcl-2 gene expression in some Pts. G3139 appears to over-come resistance to Dex/Thal with impressive clinical responses in relapsed/refractory MM patients.

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Rituximab, Fludarabine, Mitoxantrone, and Dexamethasone (R-FND) for Relapsed Indolent Lymphomas (RIL).

Blood ◽

10.1182/blood.v106.11.941.941 ◽

2005 ◽

Vol 106 (11) ◽

pp. 941-941 ◽

Cited By ~ 5

Author(s):

F.B. Hagemeister ◽

P. McLaughlin ◽

L. Fayad ◽

F. Samaniego ◽

N. Dang ◽

...

Keyword(s):

Treatment Options ◽

Median Number ◽

Autologous Stem Cell Transplant ◽

High Dose ◽

Cell Transplant ◽

Free Survival ◽

Number Of Cycles ◽

The One ◽

Indolent Lymphomas

Abstract Optimal therapy for patients (pt) with B-cell RIL remains controversial, and many treatment options include rituximab (R). Based on phase I–II studies of FND (fludarabine 25 mg/m2, d1–3; mitoxantrone 10 mg/m2, d1; dexamethasone 20 mg d1–5) treatment for RIL in which we observed a 48% CR rate, we studied the combination of R (375 mg/m2 d1) and FND for pt with RIL. Pt could not have received prior fludarabine, and were eligible if they had not previoiusly received R or had a response lasting at least 6 months (mo) to prior treament with R. Cycles were repeated every 4 weeks, and required an absolute neutrophil count of 1,000 and a platelet count of 100,000 to administer each cycle. Forty-two pt were entered onto this trial; however, one never received therapy after signing consent, and two were deemed ineligible after signing consent because of low cardiac ejection fractions (EF). All pt underwent biopsy prior to therapy; histologies included follicular gr1–3 in 30 pt, small lymphocytic in 7, marginal zone in 2. The median age was 58 (range 39–84) and median prior therapies 1 (range 1–3). The median number of cycles of R-FND delivered per patient was 6 (range 1–8). Of the 39 eligible and evaluable pt, 19 entered CR and 9 CRu for a CR/CRu rate of 72%, and 9 entered PR (23%) for an overall response rate of 95%. One had stable disease (SD), and one progression (PD). Eight underwent high dose therapy followed by autologous stem cell transplant (SCT) following a response to R-FND therapy. Five of these had achieved CR/CRu with R-FND after 1–6 cycles, and 3 PR after 2–6 cycles. In all, 14 of the 37 responders to R-FND (37%) have had progression; however, none of the 8 who underwent SCT has had progression, nor has the one with SD. In, 24 (62%) still remain free of progression with a median follow-up for living pt of 32 mo. In all, 6 pt have died of PD, including 4 who were ineligible for or refused SCT. The 2-year failure-free survival (FFS) and overall survival (OS) results for all pt are 66% and 90%. The 2-year FFS for responders is 66%, and the 2-year OS for all pt, with pt undergoing SCT censored at time of SCT is 81%. As expected, the main toxicity following R-FND was hematologic: gr 4 neutropenia occurred in 15 pt and in 15 of 130 cycles for which information is available, and gr 3–4 thrombocytopenia in 5 pt and in 6 cycles. In all, 13 of the 28 responders received less than 6 cycles of therapy; reasons included prolonged thrombocytopenia in 4, early SCT in 6, asymptomatic decrease in EF in one, and physician’s choice in 2. No patients died of acute toxicity while receiving R-FND. We conclude that 1) R-FND is a very active and well tolerated regimen for relapsed indolent lymphomas 2) Results appear very favorable compared to prior studies with FND 3) In this population, patients receiving R-FND were able to undergo SCT, and had very favorable outcomes.

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