Phase I dose-escalation study of AlphaMedix for targeted-alpha-emitter therapy of PRRT-naive neuroendocrine patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4117-4117
Author(s):  
Ebrahim Delpassand ◽  
Izabela Tworowska ◽  
Rouzbeh Esfandiari ◽  
Julien Torgue ◽  
Jason Daniel Hurt ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Dose Escalation ◽  
Objective Response ◽  
Substantial Reduction ◽  
Tumor Burden ◽  
Dramatic Improvement ◽  
Dose Escalation Study ◽  
Recist 1.1 ◽  
Alpha Emitter

4117 Background: Peptide-receptor-radioligand-therapy (PRRT) has been shown to increase the progression-free-survival (PFS) of neuroendocrine patients, however the objective response rate is rather low. The targeted-alpha-emitter therapy (TAT) of NETs can increase the ORR and induce partial or complete tumor response. In this abstract, we present results of the safety and efficacy of AlphaMedix (212Pb-DOTAMTATE) done in PRRT-naïve patients with SSTR-expressing NETs (FDA IND 135150). Methods: The phase 1 dose escalation study (IND 135150) was designed according to a 3+3 dose-escalation scheme (30% increase of the dose in each subsequent cohort). We enrolled PRRT naïve subjects with biopsy-proven unresectable or metastatic SSTR-expressing NETs from different primary sites (midgut, rectal, pancreas, and lung) with at least one measurable lesion. Response to treatment was measured per RECIST 1.1 criteria and the effect on quality of life was measured with the EORTC-QLQ-C30 QOL questionnaire. Results: A total of 20 PRRT naïve subjects (10 men and 10 women; median age 60 ( range 27-80)) have been treated to date. 10 subjects in MAD4 cohort received at least three cycles of 212Pb-DOTAMTATE at the highest dose level of 67.6 µCi/kg/cycle. Of these, 6/10 subjects (60%) have completed all four-cycles of treatment. Radiographic evaluation of these six-MAD4 patients reveal an ORR in 5 out of 6 subjects (83.3%) per RECIST 1.1 criteria (1CR, 4PR, 1SD) in addition to a 100% response according to 68Ga-DOTATATE-PET/CT-imaging, defined as complete resolution of SSTR-positive lesions (CR) or Partial Response (PR) defined as resolution of most active lesions or substantially decreased SUV (>25%). No progression of disease was noted in the first six subjects enrolled in the MAD4 cohort who have completed treatment. All six-patients have 100% PFS up to 22 months (for the first 3-subjects in MAD4) and up to 19 months (next 3-patients). Except for mild-to-moderate, reversible hair loss, there were no other clinically significant drug related AE, or SAE. The most frequent AEs of any grade (> 4 subjects) reported include fatigue (35%), hyperglycemia (30%), lymphopenia (30%) alopecia (30%), and diarrhea (20%). Five grade 3 AEs were reported (back pain, dysarthria, dyspnea, acute kidney injury), no grade 4 AEs, and one grade 5 AE was reported. There was a significant improvement in the quality of life, reduction of pain, shortness of breath in the majority of subjects, with increase of energy. Conclusions: This F-I-H clinical study of AlphaMedix shows that PRRT with 212Pb is feasible, well tolerated, and provides substantial reduction in tumor burden to patients with unresectable, metastatic SSTR-expressing NETs. Dramatic improvement in tumor burden and a positive impact on quality of life were seen in all of the PRRT naïve subjects who AlphaMedix at the highest dose tested. Clinical trial information: NCT03466216.

Intensive outpatient adjuvant therapy for breast cancer: results of dose escalation and quality of life.

1996 ◽  
Vol 14 (5) ◽  
pp. 1565-1572 ◽  
Author(s):  
S M Swain ◽  
J Rowland ◽  
K Weinfurt ◽  
C Berg ◽  
M E Lippman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Quality Of Life ◽  
Adjuvant Therapy ◽  
Psychosocial Adjustment ◽  
Dose Escalation ◽  
Maximum Tolerated Dose ◽  
Physical Symptoms ◽  
Self Report ◽  
Dose Escalation Study

PURPOSE A dose-escalation study was conducted to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cyclophosphamide (CY) in combination with granulocyte colony-stimulating factor (G-CSF0 and doxorubicin (DOX) given every 2 weeks for eight cycles as outpatient adjuvant therapy for node-positive breast cancer. A pilot study to assess quality of life (QOL) was performed. PATIENTS AND METHODS From March 1991 to April 1993, 19 patients were entered. Patients received escalating doses of CY intravenously (i.v.) (1,000 mg/m2, 1,500 mg/m2, 2,000 mg/m2, or 2,500 mg/m2) with DOX 40 mg/m2, G-CSF 10 micrograms/kg/d on days 2 to 12, and mesna, every 2 weeks for eight cycles. QOL was measured by the Profile of Mood States (POMS), the Psychosocial Adjustment to Illness Scale-Self Report (PAIS-SR), and a 27-item QOL scale. RESULTS The CY dose of 2,500 mg/m2 every 2 weeks elicited toxicities that required dose reductions secondary to a combination of thrombocytopenia, hematuria, and anemia that required transfusion. The dose of 2,000 mg/m2 resulted in an acceptable toxicity profile. Ninety-two percent of cycles at the 2,000-mg/m2 dose were delivered on schedule and 77% without hospitalization. QOL assessments indicated high levels of distress measured by POMS in 47%, poor overall quality of life in 40%, and significant problems with physical symptoms in less than 27% of all patients for any given cycle. CONCLUSION A dose of CY at 2,000 mg/m2 can be administered every 2 weeks with DOX and G-CSF for eight cycles in the outpatient setting with manageable toxicity. The majority of women described levels of physical symptoms and emotional distress as tolerable during treatment.

Quality-of-life questionnaire results 2 and 3 years after radiotherapy for prostate cancer in a randomized dose-escalation study

Urology ◽  
2003 ◽  
Vol 62 (4) ◽  
pp. 707-713 ◽  
Author(s):  
Darren J Little ◽  
Deborah A Kuban ◽  
Lawrence B Levy ◽  
Gunar K Zagars ◽  
Alan Pollack
Keyword(s):  
Quality Of Life ◽  
Prostate Cancer ◽  
Dose Escalation ◽  
Life Questionnaire ◽  
Dose Escalation Study ◽  
Quality Of Life Questionnaire

scholarly journals Quality of Life Analysis of a Radiation Dose–Escalation Study of Patients With Non–Small-Cell Lung Cancer

JAMA Oncology ◽  
2016 ◽  
Vol 2 (3) ◽  
pp. 359 ◽  
Author(s):  
Benjamin Movsas ◽  
Chen Hu ◽  
Jeffrey Sloan ◽  
Jeffrey Bradley ◽  
Ritsuko Komaki ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Lung Cancer ◽  
Radiation Dose ◽  
Small Cell Lung Cancer ◽  
Dose Escalation ◽  
Small Cell ◽  
Small Cell Lung ◽  
Dose Escalation Study ◽  
Life Analysis

Final results from ClarIDHy, a global, phase 3, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4069-4069
Author(s):  
Ghassan K. Abou-Alfa ◽  
Teresa Macarulla ◽  
Milind M. Javle ◽  
Robin Kate Kelley ◽  
Sam Joseph Lubner ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Primary Endpoint ◽  
Failure Time ◽  
Objective Response ◽  
Idh1 Mutation ◽  
High Rate ◽  
Double Blind Study ◽  
Double Blind ◽  
Grade 3

4069 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ̃20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (mIDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ̃780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 266-266
Author(s):  
Andrew X. Zhu ◽  
Teresa Macarulla ◽  
Milind M. Javle ◽  
Robin Kate Kelley ◽  
Sam Joseph Lubner ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Primary Endpoint ◽  
Failure Time ◽  
Objective Response ◽  
Idh1 Mutation ◽  
High Rate ◽  
Phase Iii ◽  
Double Blind Study ◽  
Grade 3

266 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ~20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (m IDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ~780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

Different Targeting Strategies for Treating Breast Cancer Bone Metastases

2018 ◽  
Vol 24 (28) ◽  
pp. 3320-3331 ◽  
Author(s):  
Iram Irshad ◽  
Pegah Varamini
Keyword(s):  
Breast Cancer ◽  
Quality Of Life ◽  
Bone Metastasis ◽  
Treatment Options ◽  
Tumor Burden ◽  
Breast Cancer Patients ◽  
Physiological Processes ◽  
Metastatic Cells ◽  
Skeletal Complications

Background: Breast cancer is the most frequently diagnosed malignancy in women worldwide. Breast cancer tends to metastasize to bone. Around 70% of the breast cancer patients eventually develop bone metastasis. After the bone invasion, metastatic cells disrupt the balance between osteoblastic and osteoclastic activities, leading to skeletal complications, characterized by pain and pathological fractures and hence worsening the patient's quality of life. Once tumor invades the bone, it is hard to treat it with, the so-far available treatments options (e.g. bisphosphonates and denosumab). Bone metastasis should be essentially controlled, in cancer treatment and there is a strong need to explore new, more efficient therapeutic targets. This review discusses the bone physiological processes and the recent advances in exploring different pathways involved in bone metastasis. Furthermore, some novel treatment options, which are under preclinical and clinical investigations, are highlighted. Conclusion: A deeper understanding of these metastatic pathways can provide oncology researchers with novel avenues for treating bone metastasis, one of the main challenges to cure breast cancer. The restoration of healthy bone environment will not only improve the patient's quality of life but also reduces the tumor burden.

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