scholarly journals Prolonged Treatment Response to Pembrolizumab in a Patient with Pretreated Metastatic Colon Cancer and Lynch Syndrome

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Matthew Keating ◽  
Lisa Giscombe ◽  
Toufic Tannous ◽  
Kevan Hartshorn
Keyword(s):  
Colon Cancer ◽  
Treatment Response ◽  
Treatment Duration ◽  
Single Agent ◽  
Prolonged Treatment ◽  
Close Monitoring ◽  
Metastatic Colon Cancer ◽  
Strong Response ◽  
Heavily Pretreated ◽  
Pretreated Patients

Pembrolizumab and other immunotherapies now play a prominent role in the treatment of metastatic colon cancer. Clinicians have achieved significant response rates even in heavily pretreated patients, particularly those with mismatched repair deficiencies. The endpoint of pembrolizumab treatment for patients who enjoy a strong response remains unclear. Herein, we present the case of a 33-year-old man with pretreated metastatic colon cancer and a prolonged treatment response of over three years to single-agent pembrolizumab even after treatment discontinuation in July 2018. Prior to pembrolizumab, he was found to have lung and liver metastases despite multiple lines of chemotherapy. With pembrolizumab, there was a persistent downtrend in CEA level and uptrend in weight. After nearly three years of pembrolizumab treatment from October 2015 through July 2018, PET scan showed no FDG-avid disease, and further treatment was placed on hold. He remains under surveillance, with CT scan in February 2019 again showing no evidence of local or metastatic disease. In patients whose treatment duration and disease course are not defined by toxicities/progressive disease but rather by sustained treatment responses, we propose that immunotherapy treatment duration be guided by close monitoring of CEA levels, weight, and clinical exams in addition to traditional imaging.

Safety and Efficacy of Bortezomib (Velcade) for the Treatment of Relapsed Classical Hodgkin’s Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2638-2638 ◽  
Author(s):  
Anas Younes ◽  
Barbara Pro ◽  
Jorge Romaguera ◽  
Nam Dang
Keyword(s):  
Platelet Count ◽  
Treatment Response ◽  
Cell Lines ◽  
Single Agent ◽  
Prior Treatment ◽  
Clinical Activity ◽  
Treatment Regimens ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3

Abstract The proteasome inhibitor bortezomib has demonstrated clinical activity in patients with multiple myeloma and different types of non-Hodgkin’s lymphoma. Its activity in patients with Hodgkin’s disease (HD) is unknown. We have recently reported that bortezomib had a significant activity against HD-derived cell lines in vitro (Zheng et al, Clin Cancer Res 2004), In four HD-derived cell lines, bortezomib induced cell cycle arrest and apoptosis in a dose and time dependent manner, irrespective of IkB gene mutations. Furthermore, bortezomib enhanced the activity of chemotherapy and TRAIL in these cell lines. Based on these encouraging preclinical results, we initiated a pilot study of single agent bortezomib in patients with relapsed classical HD. Eligibility: (1) relapsed classical HD with a measurable disease (2) At least 2 prior treatment regimens; (3) Patients with prior autologous stem cell transplant (ASCT) are eligible (4) platelet counts > 50,000/uL and ANC counts of > 1,500/uL (5) no HIV infection, or CNS involvement with HD, (6) bilirubin < 2mg/dL and creatinine < 2.5 mg/dL. Patients were treated with 1.3 mg/m2 bortezomib intravenously on days 1, 4, 8, 11 of 21-day cycles in an outpatient setting. Treatment was delayed if the Platelet counts on the day of therapy was < 30,000/mm3. After 3 cycles of bortezomib therapy patients were evaluated for treatment response. If there was no evidence of disease progression after 3 cycles of therapy, patients were allowed to receive a maximum of 6 cycles. To date, 11 patients are enrolled (6 men and 5 women), with a median age of 28 years (range: 21 to 68 years). All patients were heavily pretreated, with a median number of 5 prior treatment regimens (range 2 to 7 regimens), and all patients have previously failed ASCT. The median pretreatment platelet count was 126, 000/uL (range 66,000 – 339,000/uL). All patients received at least one dose of bortezomib and are evaluable for treatment toxicity. Treatment was reasonably well tolerated with the majority of toxic effects were of grade 1 and 2. Two patients had grade 3 dyspnea and one patient had grade 3 neutropenic fever. Progressive thrombocytopenia was the most common hematologic toxicity, which frequently caused delays in therapy. Nadir platelet count below 30,000/uL was observed in 3/11 patients during the first cycle, in 4/10 during the second cycle, and in 4/6 during the third cycle. Nadir ANC below 1000/uL was observed in 1/11 pts during cycle 1, in 2/10 during cycle 2, and in 1/6 during cycle 3. Eight patients completed the planned 3 cycles and are evaluable for treatment response. One patient achieved a partial remission and one had a minimal response. Our preliminary data demonstrate encouraging clinical activity of bortezomib in this heavily pretreated patients with classical HD, and warrants studying bortezomib in less heavily pretreated patients either as a single agent or in combination with chemotherapy.

Phase I/II study of iodine 131-labeled monoclonal antibody A33 in patients with advanced colon cancer.

1994 ◽  
Vol 12 (8) ◽  
pp. 1561-1571 ◽  
Author(s):  
S Welt ◽  
C R Divgi ◽  
N Kemeny ◽  
R D Finn ◽  
A M Scott ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Colon Cancer ◽  
Antitumor Activity ◽  
Phase I ◽  
Specific Activity ◽  
Gastrointestinal Symptoms ◽  
Whole Body ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Iodine 131

PURPOSE A phase I/II study was designed to determine the maximum-tolerated dose (MTD) of iodine 131-labeled monoclonal antibody (mAb) A33 (131I-mAb A33) administered intravenously, its limiting organ toxicity, and its radioisotope retention in tumors, and to develop preliminary evidence of antitumor activity. PATIENTS AND METHODS Patients (N = 23) with colorectal cancer who had failed to respond to conventional chemotherapy but had not received prior radiotherapy were treated with escalating doses of 131I-mAb A33. Three or more patients were entered at each dose level, starting at 30 mCi/m2, with increments of 15 mCi/m2 to a maximal dose of 90 mCi/m2. Radiolabeling was performed to maintain a specific activity of 30 mCi/m2/4 mg mAb A33 (projected maximum, 15 mCi/mg). Patients were under strict isolation precautions until whole-body radiation levels decreased to less than 5 mrem/h at 1 m. Serial radioimmunoscintigrams were performed in some cases for up to 3 weeks after 131I-mAb A33 administration. RESULTS All 20 patients with radiologic evidence of disease showed localization of radioisotope to sites of disease. Two patients with elevated carcinoembryonic antigen (CEA) levels and negative radiologic tests did not have positive antibody scans. One patient with a small-bowel cancer also had a negative antibody scan. The major toxicity was hematologic and was more pronounced in patients with compromised bone marrow due to prior chemotherapy. Of five patients who received 78 to 84 mCi/m2 131I-mAb A33, one had grade 3 and one grade 4 toxicity; of six patients treated with 86 to 94 mCi/m2 131I-mAb A33, two had grade 4 and one grade 1 toxicity. The MTD was determined to be 75 mCi/m2 in these heavily pretreated patients. Although the isotope showed variable uptake in the normal bowel, gastrointestinal symptoms were mild (n = 8) or absent. No major responses were observed; however, three patients had evidence of mixed responses, and CEA levels decreased in two patients without clinical or radiologic measurable disease. Immunoreactivity of radiolabeled mAb A33 decreased at the highest dose levels in preparations in which specific activity exceeded 18 mCi/mg. CONCLUSION The A33 antigen appears to be a promising target for radioimmunotherapy of colon cancer. The modest antitumor activity of 131I-mAb A33 in heavily pretreated patients is encouraging because of its lack of toxicity in the bowel, the only antigen-positive normal tissue.

scholarly journals Phase I study of obatoclax mesylate (GX15-070), a small molecule pan–Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia

Blood ◽  
2009 ◽  
Vol 113 (2) ◽  
pp. 299-305 ◽  
Author(s):  
Susan M. O'Brien ◽  
David F. Claxton ◽  
Michael Crump ◽  
Stefan Faderl ◽  
Thomas Kipps ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Chronic Lymphocytic Leukemia ◽  
Small Molecule ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Maximum Plasma ◽  
Peripheral Blood Mononuclear ◽  
Heavily Pretreated ◽  
Pretreated Patients

Abstract Obatoclax mesylate is a small molecule pan–Bcl-2 antagonist with in vitro activity against chronic lymphocytic leukemia (CLL) cells. Obatoclax was administered to patients with advanced CLL at doses ranging from 3.5 to 14 mg/m2 as a 1-hour infusion and from 20 to 40 mg/m2 as a 3-hour infusion every 3 weeks. Twenty-six patients received a total of 74 cycles. Dose-limiting reactions were neurologic (somnolence, euphoria, ataxia) and associated with the infusion. The maximum tolerated dose (MTD) was 28 mg/m2 over 3 hours every 3 weeks. One (4%) of 26 patients achieved a partial response. Patients with anemia (3/11) or thrombocytopenia (4/14) experienced improvements in hemoglobin and platelet counts. Circulating lymphocyte counts were reduced in 18 of 26 patients with a median reduction of 24%. Overall, the maximum plasma concentration (Cmax) and area under the curve (AUC) values of obatoclax were dose proportional. Activation of Bax and Bak was demonstrated in peripheral blood mononuclear cells, and induction of apoptosis was related to overall obatoclax exposure, as monitored by the plasma concentration of oligonucleosomal DNA/histone complexes. Obatoclax mesylate has biologic activity and modest single-agent activity in heavily pretreated patients with advanced CLL. Further evaluation in less heavily pretreated patients and in combination with other therapeutic agents is warranted. This trial has been registered with http://clinicaltrials.gov under identifier NCT00600964.

A phase II trial of pembrolizumab and poly-ICLC in patients with metastatic mismatch repair-proficient colon cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15552-e15552
Author(s):  
Nabin Raj Karki ◽  
Kulsum Bano ◽  
Sadek Ramses ◽  
Asha Nayak
Keyword(s):  
Colon Cancer ◽  
Mismatch Repair ◽  
Objective Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Response Rates ◽  
Metastatic Colon Cancer ◽  
Open Label ◽  
Duration Of Response

e15552 Background: Single agent programmed cell death protein 1 (PD1) inhibitor is ineffective against mismatch repair proficient (MMRp) colon cancer with response rates in single digits. Polyinosinic-Polycytidylic (Poly-ICLC) is a synthetic double stranded ribonucleic acid that generates inflammatory response increasing epitope recognition, develops tumor reactive T cells and induces interferon production which increases PD-L1 expression. In this trial, we test the effectiveness of combination of poly-ICLC and pembrolizumab in MMRp metastatic colon cancer. Methods: In this open label, single arm, single institution, phase 2 study, we enrolled 12 MMRp metastatic colon cancer patients from 1/25/2019 to 2/10/2021. Eligible patients had histologically confirmed MMRp metastatic colon cancer, ECOG 1-2 and progression on at least 2 lines of therapy. Treatment (Tx) consisted of Pembrolizumab (200 mg q3 weeks) and poly-ICLC (2 mg twice weekly, 3 days apart) for 1 year of treatment. Tx continued until progression, discontinuation or withdrawal. The primary endpoint was objective response rate by RECIST 1.1. Secondary endpoints included duration of response, adverse event profiling, progression free survival (PFS) and overall survival (OS). Intention-to-treat analyses (ITT) included all patient receiving at least one dose of the study agent. Results: 12 patients with median age 68.5 years (range 54-75) and 33% (4/12) male had been enrolled till 2/10/2021. Objective response rate was 8.3% (1 patient had partial response). The duration of response was 196 days. Among these 12 patients, median PFS was 63.5 days and median OS was 196 days. Treatment related adverse events of any grade were reported in 12/12 (100%) patients with the most common toxicities being nausea, vomiting, anorexia, dehydration and dizziness. 3/12 (25%) had serious (grade ≥ 3) toxicities and one patient died after experiencing leukocytosis, dehydration and hyperbilirubinemia attributed to the trial drugs. Conclusions: Poly-ICLC was not effective in combination with pembrolizumab for MMRp metastatic colon cancer in 3rd line setting and it did not seem to improve response rates to immunotherapy. Novel strategies for stimulating immunogenicity of cold tumors are needed. Clinical trial information: NCT02834052.

Nivolumab induces impressive responses in relapsed/refractory classic Hodgkin lymphoma: Single institutional experience

2018 ◽  
Vol 25 (7) ◽  
pp. 1586-1589 ◽  
Author(s):  
Reyad Dada ◽  
Yazeed Zabani
Keyword(s):  
Immune System ◽  
Hodgkin Lymphoma ◽  
Treatment Options ◽  
Single Agent ◽  
Classical Hodgkin Lymphoma ◽  
Activated T Cells ◽  
Serious Adverse Events ◽  
Large Patient ◽  
Heavily Pretreated ◽  
Pretreated Patients

ObjectivesCancer can escape the immune system through different mechanisms. One such mechanism is the expression of program death ligand-1 which binds to PD-1 receptor on activated T cells, subsequently leading to inhibition of the immune response against cancer cells. Nivolumab is a novel antibody that binds to PD-1 and prevents such immune tolerance. Two recently published controlled clinical trials confirmed the clinical efficacy of single-agent nivolumab in pretreated patients with classical Hodgkin lymphoma.Patients and methodsWe treated 10 heavily pretreated patients with classical Hodgkin lymphoma with the new novel PD-1 inhibitor nivolumab. We report on the outcome and safety of this agent in these patients.ResultsAfter four cycles, the response rate was 80%. Seven of 10 gained complete metabolic remission. No serious adverse events were observed. The available literature is being reviewed.ConclusionsPretreated classical Hodgkin lymphoma is amenable to novel immunotherapy. Nivolumab induces clinically meaningful responses with excellent tolerability. The drug enriches our treatment options by reviving the response of the immune system against cancer. Further controlled studies are needed to determine the effectiveness on a large patient cohort.

Low Incidence of Opportunistic Infections in CLL Patients Treated with Single Agent Flavopiridol.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3128-3128 ◽  
Author(s):  
Leslie A. Andritsos ◽  
Beth Fischer ◽  
Thomas S. Lin ◽  
Kristie A. Blum ◽  
Jeffrey A. Jones ◽  
...  
Keyword(s):  
Opportunistic Infections ◽  
Single Agent ◽  
Nucleoside Analogs ◽  
Unknown Origin ◽  
Febrile Episode ◽  
Lymphocytic Leukemia ◽  
Purine Nucleoside ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Tract Infections

Abstract Background: Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). Standard therapies such as purine nucleoside analogs and alemtuzumab have been associated with a high incidence of opportunistic infections, particularly in heavily pretreated patients. To date no studies have evaluated the incidence of infections in patients receiving flavopiridol. Study design: Patients with CLL who had relapsed following fludarabine-based therapy were eligible for participation. Treatment consisted of single agent flavopiridol administered as a 30 minute bolus followed by a 4 hour infusion weekly for 4 weeks every six weeks for up to 6 cycles. There were no exclusions for neutropenia if it was attributable to disease. All patients received prophylactic antimicrobials for prevention of HSV/VZV reactivation and P. jerovici infection unless contraindicated. Myeloid growth factors support was not utilized. Patient outcomes were retrospectively analyzed for infectious toxicities. Results: From April 2004 to August 2006 121 patients received single agent flavopiridol as part of two clinical trials. Of these, 34 patients experienced either a febrile episode or an infectious complication, or both. Twenty-four patients were male, 10 were female. There were 43 total infectious episodes in 34 patients. Of the patients experiencing an infections complication, the median number of prior therapies was 4 (range 1–11). 17 had received a purine nucleoside analog within the previous 12 months and 9 had received alemtuzumab within the previous 12 months. Of total patients treated, 5 (4%) developed pneumonia, 1 (0.8%) developed bacterial sepsis, 10 (8.3%) developed sinusitis or bronchitis, and 3 developed suspected viral respiratory infections. There were 5 (4%) skin/soft tissue infections, 7 (5.8%) catheter-related infections, and 2 (1.7%) urinary tract infections. One patient developed esophagitis and was treated empirically, as an endoscopy was contraindicated due to thrombocytopenia. Two patients were found to have aspergillus species in sputum cultures, and one of these patients had a concurrent pulmonary infiltrate. One patient experienced exacerbation of his genital HSV. No patients experienced CMV reactivation, PCP, EBV, Candida, or Legionella infections. 9 patients (7.4%) had fever of unknown origin, 5 of these in the context of cytokine release syndrome during therapy. Twenty-two episodes were associated with grade 3 or 4 neutropenia. Two patients died during infectious episodes. Conclusion: Flavopiridol is associated with an acceptable incidence of opportunistic infections when administered as a single agent, even in heavily pretreated patients. Most infections were bacterial in origin and may reflect altered immunity in patients with CLL, as well as therapy-associated myelosuppression. These results compare favorably to previous studies of infections in fludarabine-refractory patients.

Every-other week capecitabine (C7) combinations: An active and well tolerated treatment in heavily pretreated patients (p) with advanced solid tumours

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10649-10649
Author(s):  
J. Chacon ◽  
L. López ◽  
T. Quintanar ◽  
G. Rubio ◽  
M. Blanca ◽  
...  
Keyword(s):  
Single Agent ◽  
Stage Iv ◽  
Response Duration ◽  
Solid Tumours ◽  
Cancer Type ◽  
Median Response ◽  
Heavily Pretreated ◽  
N Stage ◽  
Pretreated Patients ◽  
Ecog Ps

10649 Background: Standard C schedule is 14 days every 3 w (C14). However, data have shown that C7 schedule is as effective as and significantly less toxic than C14. The objective is to evaluate retrospectively the response rate and toxicity of C7 as single agent or in combination in heavily pretreated p with advanced solid tumours. Methods: p with advanced solid tumour, age ≤ 75 years, ECOG PS <2 and adequate bone marrow, renal and hepatic functions were analyzed. p received C7: 1250 mg/m2/12 h x 7 days every-other week. The combination drugs doses were adjusted to be used days 1 and 15. Cycles every 28 days. Response was evaluated every 3 cycles according to RECIST criteria Results: 20 p received C7. Cancer type: 11 breast (BC), 7 colo-rectal (CRC), 1 H&N and 1 gastric (GC). Median age 56 y (33–75). M/F: 8p/12p. ECOG 0/1: 39%/61%. 19 p stage IV and 1 (H&N) stage III. The most frequent metastatic site was liver 42.2%. 90% p had been heavily pretreated with chemotherapy (CT): 55% p had received ≥ 2 CT lines. 15% p had been treated with taxanes, 45% p taxanes + anthracyclines, 10% p 5-FU, 15% p oxaliplatin (Oxa) and/or raltritexed. 2 BC p had also received herceptin (Her) and 2 p (1BC/1CRC) had been previously treated with C14. Median nº cycles: 6 (1–19). C7 combinations were: 5/7 CRC p Oxa or CPT-11 and 11/11 BC p docetaxel (1p) or gemcitabine (1 p) or carboplatin (9 p) ± Her. 4 p received C7 alone. Toxicity (20 p). Grade I/II: HFS 55%, diarrhoea 25%, nausea/vomiting 15%, mucositis 5%, skin 5% and parestesias 5%. Grade III/IV: diarrhoea in 2 p (1CRC and 1 BC). Response (20 p): 2 CR (10%) both CRC p; 6 PR (30%) 5 BC p and 1 CRC p; 4 SD (20%) and 8 PD (40%). 40% ORR rate and 60% TGC. Median response duration: 37 w (22–44 w). 2 p who achieved CR received C7 combined with CPT-11. C7 combination in p with PR were Oxa (1 CRC p) and carboplatin ± Her (5 BC p). Conclusions: C7 schedule is an active regimen in patients with advanced CRC and BC heavily pretreated with CT and it shows a very favourable toxicity profile. These results warrant a phase II trial of carboplatin-C7 in MBC as front line therapy that will by lauched by Feb-2006. No significant financial relationships to disclose.

AZD2171 in combination with various anticancer regimens: Follow-up results of a phase I multi-cohort study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3544-3544 ◽  
Author(s):  
A. F. Shields ◽  
E. Heath ◽  
P. DeLuca ◽  
M. Pilat ◽  
A. Wozniak ◽  
...  
Keyword(s):  
Single Agent ◽  
Preliminary Evidence ◽  
Major Effect ◽  
Preliminary Evaluation ◽  
Lung Cancers ◽  
Vegf Signaling ◽  
Simultaneous Evaluation ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Parameter Values

3544 Background: AZD2171 is an oral, highly potent and selective inhibitor of VEGF signaling. Recent trials have shown that combining a VEGF signaling inhibitor with certain chemotherapies provides clinical benefit in patients with breast, colorectal and non-small-cell lung cancers. AZD2171 was evaluated with various anticancer regimens in heavily pretreated patients with advanced solid tumors. Methods: Once-daily oral AZD2171 20 mg, 30 mg and 45 mg was given in combination with: (1) mFOLFOX6 every 2 weeks; (2) docetaxel 75 mg/m2 every 3 weeks; (3A) irinotecan 300 mg/m2 every 3 weeks; (3B) irinotecan as in 3A + cetuximab (400 mg/m2 loading dose, followed by 250 mg/m2 every week); or (4) pemetrexed 500 mg/m2 every 3 weeks. The novel study design allowed simultaneous evaluation of the safety and tolerability of these regimens with AZD2171. Secondary objectives include preliminary evaluation of potential pharmacokinetic (PK) interactions and efficacy (RECIST). Results: As of Nov 2006, 54 patients were evaluable for safety ( Table ). No unexpected toxicities were observed, and the safety profile of AZD2171 was similar to that observed in single-agent AZD2171 studies. Across all five treatment arms, common adverse events irrespective of causality included fatigue (n=46), diarrhea (n=45) and hypertension (n=21). Efficacy data were available for 39 patients, 24 of which were evaluable according to RECIST. A best overall objective tumor response of partial response (n=3) or stable disease (n=19) was observed ( Table ). AZD2171 did not appear to have a major effect on the PK profile of oxaliplatin, 5-FU, pemetrexed, irinotecan [SN38] and docetaxel. Steady-state PK parameter values of AZD2171 in this study are comparable with single-agent AZD2171 studies. Conclusion: In this group of heavily pretreated patients, combination treatment with AZD2171 and various anticancer regimens has been generally well tolerated, with no apparent PK interaction and encouraging preliminary evidence of antitumor activity. [Table: see text] No significant financial relationships to disclose.

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