Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Death

Hematologic Diseases

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Immunoglobulins

Spartalizumab

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Dose escalation of CJM112 in combination with a fixed dose of PDR001

Dose escalation of LCL161 in combination with a fixed dose of PDR001

PDR001

CJM112

LCL161

Novartis Pharmaceuticals

The purpose of this study is to assess the safety, tolerability, and identify the recommended doses of single agent CJM112, and of CJM112 or LCL161 in combination with PDR001, in patients with relapsed and/or refractory multiple myeloma.

The study is comprised of 3 treatment arms:

* Single agent CJM112 (Arm A)
* A fixed dose of PDR001 in combination with CJM112 (Arm B)
* A fixed dose of PDR001 in combination with LCL161 (Arm C)

Patients may switch from treatment on Arm A to the corresponding CJM112 dose level on Arm B at the time of disease progression if that dose level has been declared safe, and if patients do not have any DLTs on single agent CJM112. Otherwise, patients will switch to a lower dose level that has been declared safe. No other cross-over between treatment arms is allowed.

Study of Single Agent CJM112, and PDR001 in Combination With LCL161 or CJM112 in Patients With Multiple Myeloma

Phase I/Ib, Multi-center, Open-label, Study of Single Agent CJM112, and PDR001 in Combination With LCL161 or CJM112 in Patients With Relapsed and/or Refractory Multiple Myeloma

number of patients reporting dose limiting toxicity

Number of patients with treatment-related adverse events as assessed by CTCAE v4.0

Frequency of patients requiring a dose interruption

Frequency of patients discontinuing treatment.

Frequency of patients requiring a dose reduction.

Presence and/or concentration of anti-PDR001, and anti-CJM112 antibodies

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma

Urinary Bladder Neoplasms

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Transitional Cell Carcinoma

Pembrolizumab

Pembrolizumab will be administered at a flat dose of 200 mg as a 30 minute (-5 min/+10 min) IV infusion every 3 weeks (Q3W)

M.P.J.K. Lolkema

A.A.M. van der Veldt

In the RESPONDER study, the role of the immune evasive mechanisms combined with genomic characterization will be explored in urothelial cancer patients treated with second-line treatment with pembrolizumab.

Combined profiling of immune and molecular status is novel and may contribute to improved patient stratification and provide rationale for future treatment strategies containing pembrolizumab.

Antibodies that target the crosstalk between immune and cancer cells by inhibiting programmed death 1 (PD-1, Pembrolizumab and Durvalumab) or programmed death-ligand 1 (PD-L1, Atezolizumab) have shown promising results as second-line treatments in phase II studies with response rates of about 30%.

Although urothelial cancer is prone to immune checkpoint blockade, better understanding of the underlying mechanisms is necessary to improve patient selection. The efficacy of immune checkpoint inhibitors in urothelial cancer may be affected by both tumor specific and environmental factors. In order to improve the efficacy of immunotherapy in urothelial cancer, drivers of local immune suppression need to be identified.

In this prospective translational multicenter study, clinical data, peripheral blood and sequential tumor biopsies are collected from urothelial cancer patients treated with second-line treatment with pembrolizumab to identify the role of immune evasive mechanisms combined with genomic characterization. A pre-treatment tumor biopsy and blood sample will be obtained and subsequently whole genome sequencing and whole genome RNA sequencing is performed. Both tumor tissue as well as peripheral blood will be investigated for immune and molecular profiling. A biopsy will also be taken after start of treatment (at 6 weeks) and at progression (optional)

For future research projects, longitudinal blood samples will be collected for isolation of immune cells, cytokine/chemo-attractants and circulating tumor DNA (ctDNA).

Biomarkers in Urothelial Cancer Patients Treated With Pembrolizumab

Biomarker Discovery Study to Identify Patients With Advanced Urothelial Cancer Benefitting From Pembrolizumab Treatment

Information can be shared by importing it into another databases

To collect tissue, blood and urine samples for future translational experiments

Peripheral blood and sequential tumor biopsies are collected before start of treatment, during treatment, and (optionally) at progression.

Immune profiling using in situ multiplex immunofluorescence will be performed to identify tumor epithelial and stromal cells, effector immune cells, T cell co-inhibition, T cell recruitment and immune-suppressive cells. Furthermore, serum samples will be assessed for levels of cytokines/chemoattractants. Finally, longitudinal blood samples will be collected for isolation of immune cells, cytokine/chemo-attractants and ctDNA.

A qualified pathologist will determine tumor cell percentage in the obtained biopsies. DNA will be obtained from both cancer cells (biopsy tissue) and normal white blood cells (peripheral blood) and will be submitted for whole genome sequencing.

The obtained data will contribute to identifying potential biomarkers in patients with clinical benefit.

Combined profiling of immune and molecular status (as described in outcome 1) during treatment and at disease progression will reveal different mechanisms by which urothelial cancer evades pembrolizumab.

Additional bio-informatic analyses will be done to detect the somatic structural variants and copy number changes. The genome data will be used to explore potential correlations between specific pathway aberrations, total number of somatic variants and pattern of mutational load characteristic of the DNA mutational agent and clinical outcome. Moreover, we will perform whole genome RNA sequencing, an essential part of the genomic analysis to identify tumor specific neo-antigens.

The obtained data will contribute to identifying mechanisms of primary and acquired resistance to pembrolizumab.

The following definitions and response evaluation criteria will be used to assess potential correlation: immune related response criteria (irRC), duration of response according to RECIST and irRC, duration of clinical benefit (CR-complete response/PR-partial response/SD-stable disease) according to RECIST and irRC, progression-free survival, and overall survival.

By combining the data from the profiling of immune and molecular status (as described in outcome 1) with the additional data from bio-informatic analyses (as described in outcome 2) and the clinical activity (as described above), correlations between biomarkers and clinical activity can be identified.

Merck Sharp & Dohme LLC

Erasmus Medical Center

Principal Investigator

Digestive System Diseases

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Colonic Diseases

Capecitabine

Tislelizumab

Immunomodulating Agents

Thymalfasin

Adjuvants, Immunologic

Immunologic Factors

long course radiotherapy (50 Gy/25f, 2 Gy/f, 5 days/week) for the first 5 weeks and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day 8) for the first 9 weeks. After that, patients rested for two weeks (week 10-11)。6-8 weeks after the end of radiotherapy, patients underwent TME surgery (12-14 weeks). Thymalfasin was started on the first day of neoadjuvant chemoradiotherapy, 1.6 mg subcutaneously twice a week until the end of the last neoadjuvant treatment.

long course radiotherapy (50 Gy/25f, 2 Gy/f, 5 days/week) for the first 5 weeks and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day 8) for the first 9 weeks. After that, patients rested for two weeks (week 10-11)。6-8 weeks after the end of radiotherapy, patients underwent TME surgery (12-14 weeks).

Thymalfasin (thymosin-alpha 1) is an immunomodulating agent able to enhance the Thl immune response. It has been evaluated for its immunomodulatory activities and related therapeutic potential in several diseases.

It is a single-center, retrospective, controlled study to investigate the efficacy and safety of neoadjuvant chemoradiotherapy combined with PD-1 inhibitor and thymalfasin for locally advanced mid-low rectal cancer.

Study Purpose

1. To evaluate the efficacy and safety of neoadjuvant chemoradiotherapy combined with PD-1 inhibitor and thymalfasin for locally advanced mid-low rectal cancer.
2. To explore the effects of neoadjuvant chemoradiotherapy combined with PD-1 inhibitor and thymalfasin on the immune microenvironment of locally advanced mid-low rectal cancer.

Study Design: A single-center, retrospective, controlled study Subjects were divided into two groups according to whether or not they received thymalfasin: group 1 was treated with neoadjuvant chemoradiotherapy combined with PD-1 inhibitor, and group 2 was treated with neoadjuvant chemoradiotherapy combined with PD-1 inhibitor and thymalfasin.

Subjects received long course radiotherapy (50 Gy/25f, 2 Gy/f, 5 days/week) for the first 5 weeks and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day 8) for the first 9 weeks. After that, patients rested for two weeks (week 10-11)。6-8 weeks after the end of radiotherapy, patients underwent TME surgery (12-14 weeks). Thymalfasin was started on the first day of neoadjuvant chemoradiotherapy, 1.6 mg subcutaneously twice a week until the end of the last neoadjuvant treatment.

Enrollment: 26 participants, 13 in each group Study Population: locally advanced mid-low rectal cancer Primary Endpoint: pathologic complete response（pCR） Exploratory endpoint: Paraffin specimens were collected from biopsies before neoadjuvant therapy and after surgery in patients meeting the inclusion criteria. The expression of CD86, CD163, CD4+T，CD8+T，PD-1 were detected.

Pathology Paraffin Sections （Pre-NCRT and Post-NCRT）

Neoadjuvant Chemoradiotherapy Combined With PD-1 Inhibitor and Thymalfasin for Locally Advanced Mid-low Rectal Cancer

Efficacy and Safety of Neoadjuvant Chemoradiotherapy Combined With PD-1 Inhibitor and Thymalfasin for Locally Advanced Mid-low Rectal Cancer: a Single-center, Retrospective, Controlled Study

The density, H-score of each marker in paraffin-embedded tissue sections detected by mIHC

All the enrolled patients will receive total mesorectal excision (TME) 7-9 weeks after the end of long course radiotherapy. The rectal specimens will be evaluated by the pathologists who are experienced on the rectal cancer diagnosis according to the 1997 Dworak grading system. The rectal cancer will be classified into 5 grades. Grade 0-3 will be considered as non-pCR while grade 4 represent pCR.

The neoadjuvant rectal (NAR) score is a promising indicator of survival after preoperative chemoradiotherapy for rectal cancer. The NAR score was calculated according to the following formula: NAR score = \[5pN - 3(cT - pT) + 12\]2⁄9.61.

(clinical tumor (cT) stage, pathologic tumor (pT) stage, pathologic nodal (pN) stage)

AJCC 8th TRG classification. TRG 0: No viable cancer cells left in the specimen; complete regression.

TRG 1: Minimal residual cancer cells present; extensive regression with a minimal number of tumor cells.

TRG 2: Moderate residual cancer cells present; substantial regression with a significant number of tumor cells.

TRG 3: Minimal or no regression; no significant tumor cell response to treatment; majority of tumor still present.

ORR is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The ORR rate is the sum of complete response (CR) and partial response (PR)

During the surgical process, the surgeon will evaluate the level of cancer resection. It will be classified as R0, R1, R2 resection. Therefore, we can calculate R0 resection rate.

the surgeon will decide whether the anal can be preserved on the basis of the rectal cancer and intraoperative situation. anal preservation rate is the percentage of patients who achieve anal preservation.

During the 3-year follow-up, the percentage of the patients who is disease free.

During the 3-year follow-up, the percentage of local recurrence.

During the 3-year follow-up, the percentage of the patients who is sill survival at the end of follow-up.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Single Agent CJM112, and PDR001 in Combination With LCL161 or CJM112 in Patients With Multiple Myeloma	NCT03111992	Multiple Myelom...	PDR001 CJM112 LCL161	18 Years -	Novartis
Biomarkers in Urothelial Cancer Patients Treated With Pembrolizumab	NCT03263039	Transitional Ce... Biomarkers	Pembrolizumab	18 Years -	Erasmus Medical Center
Biomarkers in Urothelial Cancer Patients Treated With Pembrolizumab	NCT03263039	Transitional Ce... Biomarkers	Pembrolizumab	18 Years -	Erasmus Medical Center
Neoadjuvant Chemoradiotherapy Combined With PD-1 Inhibitor and Thymalfasin for Locally Advanced Mid-low Rectal Cancer	NCT06024356	Colorectal Neop...	Thymalfasin	18 Years -	Beijing Friendship Hospital
Study of Single Agent CJM112, and PDR001 in Combination With LCL161 or CJM112 in Patients With Multiple Myeloma	NCT03111992	Multiple Myelom...	PDR001 CJM112 LCL161	18 Years -	Novartis

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