Phase I study of SNK01 (autologous non-genetically modified natural killer cells with enhanced cytotoxicity) in refractory metastatic solid tumors.

e15024 Background: Natural Killer (NK) cells possess the innate ability to detect transformed cancer cells and kill them, thus playing a key role in cancer immunosurveillance and antitumor immunity. In general, prior NK cell therapies have not shown efficacy in solid tumors and the expansion of NK cells in cancer patients to clinically therapeutic doses is quite challenging, making allogenic preferable to autologous treatment. SNK01 is a first-in-kind, autologous non-genetically modified NK cell therapy with enhanced cytotoxicity which can be consistently produced even from heavily pretreated cancer patients, and has been shown to have efficacy against numerous solid tumor types in preclinical studies. Methods: In this single-arm Phase I study (NCT03941262) to investigate the safety and efficacy of SNK01, patients with refractory metastatic solid tumors were treated in a 3 + 3 dose escalation study with five weekly infusions of SNK01 at 1, 2, or 4 x 109 cells per infusion. Primary endpoint is safety and quality of life (QoL), and secondary endpoint is objective response rate (ORR). Results: Seven of nine planned patients have been enrolled up to date and five have completed treatment. All patients have rapidly progressive metastatic disease and have received an average of five lines of prior therapy. Tumor types include one non-small lung cancer, one colorectal cancer, and five sarcomas. Median age is 52 (32-62). All patients have had successful expansion and cytotoxic enhancement of their NK cells. Three patients have completed 1 x 109 SNK01 and two patients have completed 2 x 109 SNK01. There have been no adverse events according to NCI-CTCAE v 5.0 or any cytokine release syndrome, and all patients have reported an overall improvement in QoL. At week 9, three of three patients at the 1 x 109 dose and one of two at the 2 x 109 achieved a best overall response of stable disease as per RECIST 1.1. Conclusions: Expanding and increasing the cytotoxicity of NK cells in our heavily pretreated patients has been consistently reliable. SNK01 monotherapy has been very safe and well tolerated in patients with rapidly progressive solid tumors. MTD has not been reached and dose escalation is ongoing. Evaluation of anti-tumor activity is ongoing, but at a minimum, SNK01 appears to slow and possibly halt progression in very aggressive disease and improve quality of life while improving the overall quality of life. The remaining two planned patients are currently being enrolled and a full update will be presented. Clinical trial information: NCT03941262 .

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Phase I Trial of Lenalidomide + Vorinostat After Autologous Transplant in Multiple Myeloma.

Blood ◽

10.1182/blood.v120.21.3114.3114 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3114-3114

Author(s):

Craig C. Hofmeister ◽

Mindy A Bowers ◽

Yvonne A Efebera ◽

Kristina Humphries ◽

Don M. Benson ◽

...

Keyword(s):

Quality Of Life ◽

Phase I ◽

Nk Cells ◽

Mhc Class I ◽

Phase I Trial ◽

Nk Cell ◽

Brief Pain Inventory ◽

Peripheral Blood Flow ◽

Post Transplant

Abstract Abstract 3114 Introduction: Post autologous transplant maintenance therapy for patients with multiple myeloma (MM) is standard of care (McCarthy et al, NEJM, 2012). Vorinostat (SAHA, Zolinza) is a HDAC inhibitor for which preclinical evidence suggests that its combination with bortezomib is synergistic via HDAC-6. Preclinical data suggests that HDAC-I's increase MHC class I and class II expression, rendering tumor cells more susceptible to host innate immune killing. Lenalidomide activates NK cells via PP2A inhibition and induces CD56 expression in CD16+CD56- cells thereby enhancing NK cell-mediated ADCC. Initiating lenalidomide to enhance NK cell activity against tumor cells in the early post transplant period, especially if administered after increased MHC class I expression induced by HDAC-I pretreatment. We hypothesized that the combination of Vorinostat and lenalidomize would be both tolerable and effective post-transplant. Methods: This was a phase I trial for myeloma patients after hematopoietic stem cell transplant (HSCT) following the 3×3 phase I design. Patients were required to have an ANC3 1000/μL, platelet count3 75,000/μL, and a serum creatinine2 1.5x institutional upper limit of normal. Vorinostat was administered starting day +90 after HSCT for days 1–7 and 15–21 starting at 200 mg and escalating to a max of 400 mg combined with lenalidomide 10 mg days 1–21 of a 28-day cycle until progression or clinically significant toxicity. Lenalidomide could be escalated after cycle 1 in 5 mg increments to a maximum of 25 mg. The primary endpoint was maximum tolerated dose (MTD) and dose limiting toxicities were assessed during the first cycle. Correlative endpoints included quality of life assessments with the Brief Pain Inventory (Short Form), The Center for Epidemiologic Studies Depression Scale (CES-D-10), Brief Fatigue Inventory (BFI), Brief Pain Inventory (BPI), and the FACT-G. Peripheral blood flow cytometry for NK cells and Tregs were obtained day 1 of the first cycle of combined therapy (C1D1/3 mos. post transplant), C2D1 (4 mos.), C3D1 (5 mos.), C4D1 (6 mos.), and off study. Results: Sixteen patients were enrolled after HSCT with a median age 58 y.o. (range 41–67) with a median number of prior therapies at enrollment of 2 (range 1–8) and mean ISS stage 1.5 (range 1–3). Twelve patients had only trisomies on CD138-selected FISH, one patient had normal cytogenetics, and three patients had high risk features [complicated karyotype, t(4;14), or abnormal chromosome 1]. Median follow-up has not been reached. Fifteen patients received more than one cycle of therapy. 11/15 (73%) were able to escalate the lenalidomide dose with 4/11 (36%) reaching the maximum lenalidomide dose, and all but 1 of the 11 required lenalidomide dose reduction due to subsequent neutropenia. Of the adverse events possibly, probably, or definitely related to therapy (table 1), the most common toxicities were neutropenia (11.8% of all AEs), fatigue (11.1%), thrombocytopenia (9.7%), diarrhea (7.6%), anemia (6.9%), hypokalemia (6.3%), and rash (4.9%). Infection with a normal ANC occurred only twice and no patient suffered a DVT. One patient had therapy stopped due to toxicities, one due to progressive disease, and one due to megacolon that was present prior to transplant. Four patients improved their transplant response after starting lenalidomide/vorinostat. Preliminary analysis of quality of life from the start of therapy through the first three cycles found no significant change in the BFI, FACT-G, CES-D, or BPI. Conclusions: Lenalidomide/vorinostat post HSCT was well tolerated and 14/16 (87%) of patients remain on protocol therapy. There were no DLTs and patients the final cohort starting at 400 mg vorinostat and 10 mg lenalidomide completed accrual. The median dose of lenalidomide for those patients receiving maintenance therapy 1 year post-transplant is 5 mg daily. Analysis of peripheral blood flow NK cells and Tregs, cumulative dose intensity, and median progression free survival will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

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Immune Activation and Anemia Are Associated with Decreased Quality of Life in Patients with Solid Tumors

Journal of Clinical Medicine ◽

10.3390/jcm9103248 ◽

2020 ◽

Vol 9 (10) ◽

pp. 3248

Author(s):

Patricia Kink ◽

Eva Maria Egger ◽

Lukas Lanser ◽

Michaela Klaunzner ◽

Bernhard Holzner ◽

...

Keyword(s):

Quality Of Life ◽

Cancer Patients ◽

Solid Tumors ◽

Immune Activation ◽

Inflammatory Markers ◽

Mild Depression ◽

Tryptophan Degradation ◽

Immune Mediated ◽

Phenylalanine Metabolism

Anemia often coincides with depression and impaired quality of life (QoL) in cancer patients. Sustained immune activation can lead to the development of anemia. Furthermore, it also may go along with changes in tryptophan and phenylalanine metabolism. The aim of our pilot study was to study the relationship between anemia, immune-mediated changes in amino acid metabolism, and the QoL and mood of cancer patients. Questionnaires to measure QoL and depression were completed by 152 patients with solid tumors. Hemoglobin, parameters of immune activation as well as tryptophan and phenylalanine metabolism were determined in the patients’ sera. Anemic patients (51.7%) presented with higher inflammatory markers, and a higher tryptophan breakdown with lower tryptophan concentrations. They reported an impaired QoL and had higher depression scores. Patients with an impaired QoL (65.8%) also suffered from more fatigue and impaired physical, emotional, and social functioning. They, furthermore, presented with higher concentrations of inflammatory markers (C-reactive protein (CRP) and neopterin) as well as higher tryptophan degradation (in men) and higher phenylalanine concentrations (in women). Sixty-one patients (40.1%) had (mostly mild) depression. In these patients, a higher degree of Th1 immune activation was found. The results of our study suggest that cancer-related anemia goes along with an impaired QoL, which is also associated with immune-mediated disturbances of tryptophan and phenylalanine metabolism.

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Quality-of-Life Priorities in Patients with Thyroid Cancer: A Multinational European Organisation for Research and Treatment of Cancer Phase I Study

Thyroid ◽

10.1089/thy.2015.0640 ◽

2016 ◽

Vol 26 (11) ◽

pp. 1605-1613 ◽

Cited By ~ 15

Author(s):

Susanne Singer ◽

Olga Husson ◽

Iwona M. Tomaszewska ◽

Laura D. Locati ◽

Naomi Kiyota ◽

...

Keyword(s):

Quality Of Life ◽

Thyroid Cancer ◽

Phase I ◽

Phase I Study ◽

European Organisation

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Safety, tolerability and immunogenicity of V934/V935 hTERT vaccination in cancer patients with selected solid tumors: a phase I study

Journal of Translational Medicine ◽

10.1186/s12967-020-02228-9 ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 3

Author(s):

Luigi Aurisicchio ◽

Arthur Fridman ◽

David Mauro ◽

Rose Sheloditna ◽

Alberto Chiappori ◽

...

Keyword(s):

Phase I ◽

Cancer Patients ◽

Solid Tumors ◽

Phase I Study

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Subjective symptoms and quality of life in healthy subjects during a phase I study

European Journal of Clinical Pharmacology ◽

10.1007/s002280050186 ◽

1996 ◽

Vol 51 (3-4) ◽

pp. 215-219 ◽

Cited By ~ 4

Author(s):

R. Schüppel ◽

B. Boos ◽

G. Bühler ◽

M. Lataster ◽

T. Peters

Keyword(s):

Quality Of Life ◽

Phase I ◽

Healthy Subjects ◽

Phase I Study ◽

Subjective Symptoms

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The quality of life of cancer patients participating in phase I clinical trials using SEIQoL‐DW

Journal of Advanced Nursing ◽

10.1046/j.1365-2648.1999.01079.x ◽

1999 ◽

Vol 30 (2) ◽

pp. 335-343 ◽

Cited By ~ 26

Author(s):

Sophia Campbell ◽

Fiona Whyte

Keyword(s):

Quality Of Life ◽

Clinical Trials ◽

Phase I ◽

Cancer Patients ◽

Phase I Clinical Trials

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Immune Reconstitution and Quality of Life Analyses After Autologous Transplant for Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.4460.4460 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4460-4460

Author(s):

Craig C. Hofmeister ◽

Mindy A Bowers ◽

Anissa Bingman ◽

Gerard Lozanski ◽

Robert A. Baiocchi ◽

...

Keyword(s):

Quality Of Life ◽

T Cells ◽

Nk Cells ◽

Peripheral Blood ◽

Nk Cell ◽

Anxiety And Depression ◽

Time To Progression ◽

Post Transplant ◽

One Year

Abstract Abstract 4460 Introduction: Multiple myeloma patients after autologous hematopoietic stem cell transplant (HSCT) achieve a minimal residual disease state, providing an opportunity for immunomodulatory therapy – but the details of immune recovery after transplant are not clear. Early lymphocyte recovery is associated with improved overall survival (Porrata et al, 2003) which is thought to be related to NK cell recovery. Myeloma patients with long term disease control have recovered circulating B-cells, bone marrow dendritic cells and tissue macrophages similar to healthy adults, but have few circulating regulatory T-cells (Pessoa et al, Haematologica, 2012). Methods: This trial assessed immune function as measured by response to the conjugate vaccine to Streptococcus pneumoniae (Prevnar, PCV7), detailed peripheral blood lymphocyte subset analysis (including NK cell subsets and Tregs), as well as quality of life measures (Hospital Anxiety and Depression Scale, Brief Fatigue Inventory [BFI], Brief Pain Inventory [BPI], and the FACT-G) after autologous transplant for myeloma. Myeloma patients after either 140 or 200 mg/m2 melphalan HSCT were enrolled if they had ANC ≥1000/μL, platelet count ≥ 75,000/μL, and adequate hepatic function by the time Prevnar [serotypes 4, 9V, 14, 18C, 19F, 23F, and 6B] was administered on weeks 9 [month 2], 17 [month 4], and 25 [month 6] after autologous HSCT. Maintenance therapy was an exclusion criteria. Results: Thirty patients were enrolled – twelve with ISS stage 1 at diagnosis, six with ISS 2, five patients with ISS 3, and nine were unknown. Disease status pre-transplant revealed 34% CR and 78% ≥PR, at +60 days 44% CR and 94% ≥PR, but by +180 days the ≥PR was down to 76% due primarily to relapses from CR. With a median follow-up of 35 months since diagnosis and 28 months since transplant, median time to progression has not been reached. We used ELISA to assess antibody concentration against immunogenic antigens (14 & 18c) and the less immunogenic antigen 23F. Two months after each PCV7 injection [weeks 13, 25, and 33], an adequate response (>35 mcg/mL) was demonstrated for antigen 14 in 7% (2/29) at week 13, 16% (4/25) at week 25, and 19% (5/27) at week 33. For antigen 18C, 6.7% (2/30) at week 13, 8.3% (2/24) at week 25, and Z% (4/26) at week 33. At one year responses faded with only 10% (2/20) for antigen 14, 0% (0/24) for antigen 18C, and 0% (0/7) for antigen 23F. Quality of life analyses including BFI, FACT-G, BPI, and HADS showed no significant changes from weeks 9, 17, 25, and off study except for worsening anxiety and depression at one year post-transplant compared to study entry. Peripheral blood flow cytometry using Cox univariate analysis showed an association with overall survival with late activated T-cells (CD3+HLA-DR+, p<0.05 at 30 days and p<0.01 at 100 days) and degranulated T-cells (CD3+CD63+,p<0.09 at 30 days, p<0.06 at 100 days. An association with the achievement of CR at day +30 post-transplant was seen for NK cells (CD3-CD16+CD56+, p<0.024), KIR- NK cells (CD3-CD16+CD56+CD158b-, p<0.07), and CD314+ NK-cells (CD3-CD16+CD56+CD314+, p<0.04. Calculating Spearman correlation coefficients between lymphocyte subsets and Prevnar antibody response found no lymphocyte subset associated with response in more than one antigen. Conclusions: In this pilot trial of 30 myeloma patients we have shown that the adaptive immune system is profoundly suppressed with a minority of patients reacting to the conjugate vaccine Prevnar. Depression and anxiety both worsen in the first year post transplant. Multivariate and grouped covariate analyses of peripheral blood lymphocyte subsets with both Prevnar response and time to progression will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

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Phase I study to assess the safety, tolerability, pharmacokinetics/pharmacodynamics and preliminary efficacy of SC10914 in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6047 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6047-6047

Author(s):

Jifang Gong ◽

Jinhai Tang ◽

Yongmei Yin ◽

Dingwei Ye ◽

Jian Zhang ◽

...

Keyword(s):

Ovarian Cancer ◽

Phase I ◽

Cancer Patients ◽

Solid Tumors ◽

Phase I Study ◽

Advanced Solid Tumors ◽

Dose Escalation Study ◽

Adequate Organ Function ◽

Grade 3 ◽

Wbc Count

6047 Background: SC10914 is a highly selective inhibitor of PARP enzymes, including PARP1 and PARP2. SC10914 has a similar structure with olaparib. We conducted a phase I study to assess the safety, tolerability, PK/PD and preliminary efficacy of SC10914 in patients with advanced solid tumors. Methods: This is a phase I dose-escalation study with 3+3 design, we enrolled patients at 4 sites in China. Eligible patients were diagnosed with advanced solid malignancies who are refractory to standard therapies or for which no standard therapy exists; had measurable disease; had adequate organ function. Patients received SC10914 daily at ten escalating doses from 30 mg QD to 500 mg TID in a 28-day cycle. We obtained blood for PK and CA125 assessments. Toxic effects were assessed by CTCAE 4.03 criteria and tumour responses ascribed by RECIST 1.1 and CA125 was assessed by GCIG criteria. Results: As of January 2020, 52 patients were enrolled, of which 14 were males and 38 were females. Ten doses were escalated to 500mg TID, and no DLT was observed, and MTD was not obtained. The incidence of grade 3/4 AEs and SAEs that were related to SC10914 were 34.6% (18/52) and 13.5% (7/52). Grade 3/4 adverse reaction happened in at least two patients were anaemia/reduced hemoglobin (10/52, 19.2%), decreased WBC count (5/52, 9.6%), neutropenia (3/52, 5.8%), thrombocytopenia (2/52, 3.8%), and decreased lymphocyte count (2/52, 3.8%). A total of 17 gBRCAm evaluable ovarian cancer patients were enrolled, 6 of them had PR, the ORR was 35.3% (6/17). 10 gBRCAm ovarian cancer patients were enrolled in TID groups (including 2 patients who received BID doses at the beginning and changed to 300 mg TID dose after several cycles of treatment), 5 of them had PR, the ORR was 50% (5/10). The ORR of 400 mg TID group was 66.7%(4/6). PK data showed that the exposure of SC10914 was increased with dose increasing at the dose of 30 mg to 250 mg. The half-life of SC10914 was about 2-5 hours. Conclusions: SC10914 was safe in patients with advanced solid tumors. The main toxicity was blood-related adverse reactions. SC10914 was effective in gBRCAm ovarian cancer patients. 400 mg TID might be RP2D. Clinical trial information: NCT02940132.

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