Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

Azacitidine

Nivolumab

Relatlimab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Antimetabolites

Enzyme Inhibitors

5-azacitidine 75 mg/m2 body surface area s.c. for 7 days nivolumab 480mg i.v. day 1 relatlimab 80-160mg i.v. day 1

repeat day 28

Azacitidine Injection

Marion Subklewe, MD

Veit Bücklein, MD

The clinical trial will test the safety and tolerability of a combination therapy (azacitidine in combination with two checkpoint inhibitors, nivolumab \[Anti-PD1\] and relatlimab \[Anti-LAG3\]) in patients with relapsed/refractory Acute Myeloid Leukemia (AML) and patients ≥ 65 years with initial diagnosis of AML.

Primary objectives are:

* maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the combination therapy during the lead-in phase of the clinical trial (6-12 patients) and
* objective response rate (ORR) of the combination therapy in the phase II part of the study (up to 24 patients).

Relatlimab With Nivolumab and 5-Azacytidine for the Treatment of AML

An Open-Label Phase II Study of Relatlimab (BMS-986016) With Nivolumab (BMS-936558) in Combination With 5-Azacytidine for the Treatment of Patients With Refractory/Relapsed Acute Myeloid Leukemia and Newly Diagnosed Older Acute Myeloid Leukemia Patients

To study immunological changes in the peripheral blood and bone marrow in response to relatlimab + nivolumab + 5-azacytidine therapy, assessed by the frequency of T-cell (subsets), regulatory T cells, and immune checkpoint expression on blasts and T cells by flow cytometry and RNA Sequencing

To study the methylation status of blast DNA in the peripheral blood and bone marrow in response to relatlimab + nivolumab + 5-azacytidine therapy

To determine the MTD of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML.

To determine the DLT of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML.

To estimate the ORR to treatment with relatlimab + nivolumab + 5-azacytidine in patients with R/R AML and Patients ≥65 years with initial diagnosis of AML

To determine the number of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine who have a hematologic improvement (HI) in platelets, hemoglobin, or absolute neutrophil count (ANC)

To determine the number of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine who have a blast reduction (defined as ≥50% reduction in blast percentage compared to baseline blast percentage in bone marrow)

To assess the duration of response (DOR) of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine.

To assess the disease-free survival (DFS) of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine.

To assess the overall survival (OS) of patients with R/R AML or Patients ≥65 years with initial diagnosis of AML treated with relatlimab + nivolumab + 5-azacytidine.

Ludwig-Maximilians - University of Munich

Investigator

Symptoms and General Pathology

Nervous System Diseases

Glioma

Shock

Diffuse Intrinsic Pontine Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Brain Stem Neoplasms

Infratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Neuroepithelioma

Micronutrients

Anti-Infective Agents

Antibodies

Antibodies, Monoclonal

Vaccines

Immunomodulating Agents

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Myeloma Proteins

Paraproteins

Iodine

Cadexomer iodine

Immunologic Factors

Anti-Infective Agents, Local

Trace Elements

rHSC-DIPGVax (8 total doses) + BALSTILIMAB (1 year of therapy or 27 cycles, whichever comes first)

Patients will enroll 6-10 weeks post standard of care (SOC) radiation completion. Steroid dose must be at or below 0.5mg/kg/day for a minimum of 7 days. The first 3 patients must be 5 years or older to 18. Subsequently, subjects ages 12 months to 18 years can be enrolled. Up to six patients will be enrolled on Part A. Once safety is established for rHSC-DIPGVax plus anti-PD1 (BALSTILIMAB), the study will proceed to Part B.

rHSC-DIPGVax (8 total doses) + BALSTILIMAB + ZALIFRELIMAB (1 year of therapy or 9 cycles, whichever comes first)

Patients will enroll 6-10 weeks post standard of care (SOC) radiation therapy. Steroid dose must be at or below 0.5mg/kg/day for a minimum of 7 days. The first 3 patients must be 5 years or older to 18. Subsequently, subjects ages 12 months to 18 years can be enrolled. Up to 12 patients will be enrolled on Part B. Once safety is established for rHSC-DIPGVax plus anti-PD1 (BALSTILIMAB) plus anti-CTLA4 (ZALIFRELIMAB), the study will proceed to Part C.

rHSC-DIPGVax (8 total doses) + BALSTILIMAB + ZALIFRELIMAB (at RP2D from Part B) (1 year of therapy or 9 cycles, whichever comes first)

Patients will enroll 6-10 weeks post standard of care (SOC) radiation therapy. Steroid dose must be at or below 0.5mg/kg/day for a minimum of 7 days. Up to 12 patients will be enrolled on Part C. All subjects in Part C will be monitored for DLT's for the duration of their participation in the study to monitor for excess toxicity.

Off-the-shelf, neoantigen heat shock protein vaccine

rHSC-DIPGVax

BALSTILIMAB is a human monoclonal antibody that targets programmed cell death 1 (PD1)

Balstilimab

ZALIFRELIMAB is a human monoclonal immunoglobulin G1k subclass (IgG1k) antibody that specifically recognizes cytotoxic T lymphocyte-associated protein 4 (CTLA-4, also known as CD152)

Zalifrelimab

George Rafidi, BS

Ashley Plant-Fox, MD

Mariko Sato, MD

Claudia Mousa

Ashley S Plant, MD

Alexa E Stathis

Susan Chi, MD

This is a phase I, open label, plus expansion clinical trial evaluating the safety and tolerability of rHSC-DIPGVax in combination with BALSTILIMAB and ZALIFRELIMAB. rHSC-DIPGVax is an off-the-shelf neo-antigen heat shock protein containing 16 peptides reflecting neo-epitopes found in the majority of DIPG and DMG tumors. Newly diagnosed patients with DIPG and DMG who have completed radiation six to ten weeks prior to enrollment are eligible.

This is a phase I, open label, plus expansion clinical trial evaluating the safety and tolerability of rHSC-DIPGVax in combination with BALSTILIMAB and ZALIFRELIMAB using a 3+3 design for subjects with newly diagnosed DIPG or DMG following completion of radiation therapy. Given this is a first in-human study of rHSC-DIPGVax, an initial study "Lead In" will assess the tolerability of vaccine monotherapy first in older children (ages 5 to 18 years of age) followed by younger children (12 months to 18 years of age).

Sequential Parts A and B of this study will also first enroll patients ages 5 to 18 years of age before enrolling younger children. The rationale for the combination of vaccine and anti-PD1 therapy includes evidence of a more profound intra-tumoral response with addition of inhibition of negative co-regulatory pathways, such as, PD1/PDL1 and the need to overcome potentially immunosuppressive or immune "cold" microenvironment of gliomas. Anti-CLTA4 therapy will also be combined with rHSC-DIPGVax in the dose escalation portion of this study because of the ability of anti-CTLA4 therapy to induce T cell priming to promote T memory formation. Given the lack of standard treatment options for DIPG and DMG patients, this clinical trial will use combinatorial immunotherapy in upfront treatment of these patients in hopes of maximizing potential efficacy in this at-risk population while still assessing safety throughout.

Part A will evaluate rHSC-DIPGVax plus BALSTILIMAB. Pharmacokinetics (PK) of BALSTILIMAB will also be evaluated to assess exposure. If the rHSC-DIPGVax plus BALSTILIMAB is well tolerated in Part A for 28-days, this study will then move to enrolling Part B to evaluate the safety and tolerability of rHSC-DIPGVax and BALSTILIMAB in combination with ZALIFRELIMAB at two dose levels for a total therapy duration of one year or twenty-seven cycles, whichever occurs first.

Advancement from Part A to Part B and dose escalation in Part B will follow a conservative 3+3 design. The dose limiting toxicity (DLT) monitoring period will last 28 days (2 cycles) for Part A subjects and 42 days (1 cycle) for Part B. Subjects will be allowed to continue on in Part A for twenty-seven 14-day cycles or nine 42-day cycles in Part B or 1 year of total therapy, whichever comes first.

After the RP2D of ZALIFRELIMAB is determined, Part C, the expansion arm, will enroll further subjects at this dose level to assess futility versus efficacy. All subjects in trial Part C will be monitored for dose limiting toxicities for the duration of their participation in the study to monitor for excess toxicity.

Phase I, open label, plus expansion clinical trial

rHSC-DIPGVax Plus Checkpoint Blockade for the Treatment of Newly Diagnosed DIPG and DMG

A Phase I Clinical Trial of Neo-antigen Heat Shock Protein Vaccine (rHSC-DIPGVax) in Combination With Checkpoint Blockade for the Treatment of Diffuse Intrinsic Pontine Glioma (DIPG) and Diffuse Midline Glioma in Childhood

PBMC immune subsets measured via flow cytometry from peripheral blood samples

peak plasma concentration (Cmax) of BALSTILIMAB AND ZALIFRELIMAB in the blood

Area under the plasma concentration versus time curve (AUC) of BALSTILIMAB AND ZALIFRELIMAB in the blood

Assays to assess anti drug antibody levels in the blood

Number of DLT's per CTCAE version 5.0 and iRANO guidelines.

Number of DLT's using CTCAE version 5.0 and iRANO guidelines

Overall survival from time of diagnostic imaging to time of death

time to progression (from time of diagnostic imaging to time of disease progression)

Dana-Farber Cancer Institute

Children's Hospital of Orange County

University of Calgary

Ann & Robert H Lurie Children's Hospital of Chicago

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Neoplasm Metastasis

Carcinoma

Recurrence

Carcinoma, Renal Cell

Kidney Neoplasms

Adenocarcinoma

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Ipilimumab

Neoadjuvant 2 cycles of nivolumab 360mg every 3 weeks

Neoadjuvant 2 cycles of nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks

Neoadjuvant 2 cycles of nivolumab 360mg + relatlimab 360mg every 3 weeks

Patients will receive 2 cycles of nivolumab 360mg (arm A and C) or 3mg/kg (arm B) every 3 weeks followed by a nephrectomy.

Neoadjuvant nivolumab

Patients will receive 2 cycles of ipilimumab 1mg/kg every 3 weeks followed by a nephrectomy.

Neoadjuvant ipilimumab

Patients will receive 2 cycles of relatlimab 360mg every 3 weeks followed by a nephrectomy.

Neoadjuvant relatlimab

John Haanen, Prof

Femke Burgers, MD

Axel Bex, Prof

The NESCIO-trial is a multicenter, randomized, open-label, three-arm phase II trial investigating different combinations of neoadjuvant immunotherapy in patients with primary, resectable, intermediate to high-risk, clear-cell renal cell carcinoma. In this trial patients will be randomized 1:1:1 to receive either 2 cycles of nivolumab 360mg every 3 weeks (arm A), 2 cycles of ipilimumab 1 mg/kg + nivolumab 3 mg/kg every 3 weeks (arm B) or 2 cycles of relatlimab 360mg + nivolumab 360mg every 3 weeks (arm C), prior to surgery at week 7.

After 42 patients (14 per arm) have been recruited, an interim analysis will be performed to evaluate the observed efficacy and toxicity within each arm and either allow for early discontinuation of the treatment or continuing recruitment for the second stage. As the primary endpoint, the pathological response (decrease in tumor) will be evaluated. If at most one pathologic response in the primary tumor is observed, the treatment arm will be closed for insufficient activity on the primary tumor. If at least 2 pathologic responses are observed, 9 additional patients will be included to a total of 23 patients per cohort. A maximum of 69 patients will be recruited for this study.

Follow up will start at week 12 with a CT-scan according to the national/center's standard. Patients will be evaluated every 3 months by physical examination and lab testing for up to two years, thereafter according to institutional guidelines up to 5 years following surgery.

Open-label three-arm randomized phase II trial

Neoadjuvant Study With Combination Immuno-oncology for Primary Clear Cell Renal Cell Cancer

Prospective, Randomized, Neoadjuvant Phase II Study With Combination Immuno-oncology in Primary Clear Cell Renal Cancer at Risk for Recurrence or Distant Metastases (NESCIO-trial)

Pathologic response rate is defined as the proportion of patients demonstrating a complete pathologic or partial pathologic response, according to central revision (pathology of NKI)

ORR is defined as the proportion of patients demonstrating a complete or partial response according to RECIST 1.1

RFS is defined as the time from randomization to recurrence or death from any cause, whichever occurs first. Subjects last known to be alive, who have not experience recurrence, will be censored.

EFS is defined as the time from randomization to recurrence, distant metastasis, or death from any cause, whichever occurs first. Subjects who are event-free at the end of follow-up will be censored.

The proportion of patients starting treatment who experience distant metastases during follow-up.

The proportion of patients starting treatment who experience a local recurrence during follow-up.

Surgical complication rates according to Clavien-Dindo classification

Bristol-Myers Squibb

The Netherlands Cancer Institute

Skin and Connective Tissue Diseases

Melanoma

Neuroendocrine Tumors

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Trametinib

Dabrafenib

2 cycles of neoadjuvant ipilimumab (80mg) + nivolumab (240mg) every 3 weeks followed by a total lymph node dissection (TLND) and if applicable, resection of in-transit metastases.

Patients with a pathologic partial or non-response in arm A will also receive adjuvant nivolumab 480 mg every 4 weeks 11 cycles. In case of BRAF V600E/K mutation-positivity, patients will be treated with adjuvant dabrafenib plus trametinib for 46 weeks instead.

Standard upfront total lymph node dissection (TLND) and if applicable, resection of in-transit metastases followed by 12 cycles adjuvant nivolumab 480 mg every 4 weeks

2 cycles ipilimumab (80mg) + nivolumab (240mg) every 3 weeks followed by total lymph node dissection

Neoadjuvant ipilimumab + nivolumab

Upfront total lymph node dissection followed by 12 cycles of nivolumab (480mg) every 4 weeks.

Adjuvant nivolumab

Christian Blank, Prof

Georgina Long, Prof

This is an international (Australia, Europe, and USA) open-label two-arm randomized phase 3 trial including 420 stage III (≤3 resectable in-transit metastases allowed) cutaneous or unknown primary melanoma patients. Patients will be randomized 1:1 to receive either 2 cycles of neoadjuvant ipilimumab 80 mg + nivolumab 240 mg every 3 weeks followed by a total lymph node dissection (TLND) and, if applicable, resection of in-transit metastases (arm A) versus standard upfront TLND +/- resection of in-transit metastases followed by 12 cycles adjuvant nivolumab 480 mg every 4 weeks (arm B). Patients with a pathologic partial or non-response in arm A will also receive adjuvant nivolumab 480 mg every 4 weeks for 46 weeks (11 cycles). In case of BRAF V600E/K mutation-positivity, patients from arm A with a pathologic partial or non-response (\>10% viable tumor) will be treated with adjuvant dabrafenib plus trametinib for 46 weeks. Patients will be treated in the study in both arms until melanoma progression to irresectable stage III or stage IV disease, disease recurrence, unacceptable toxicity, subject withdrawal of consent or until end of study treatment.

An interim analysis will be performed after 60 events have occurred. The data safety monitory board (DSMB) will be ad hoc consulted when unexpected toxicities are reported. Patients will be followed by 12 weekly CT scans until end of year 3 and then until year 5 according to the institute's standards.

Open-label two-arm randomized phase 3 trial

Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma

Multicenter Phase 3 Trial Comparing Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma - NADINA

EFS is defined as time from randomization to melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, treatment-related death, or melanoma-related death, whichever occurs first. Occurrence of a new primary melanoma during treatment/follow-up is also regarded as an event. Presurgical resectable progression to stage III disease in arm A is not defined as an event, even as death to another reason than melanoma or the study treatment.

RFS is defined as time between date of surgery and date of melanoma recurrence, treatment-related death or melanoma-related death, whichever occurs first.

DMFS is defined as time between date of randomization and date of first distant metastasis, treatment-related death or melanoma-related death, whichever occurs first.

OS is defined as time between date of randomization and date of death.

The pathologic response rate will be categorized into pathologic complete response (pCR), near-pCR, major pathologic response (MPR), pathologic partial response (pPR), pathologic no response (pNR), according to International Neoadjuvant Melanoma Consortium (INMC) criteria.

Frequency of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.

Duration of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.

Type of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.

Surgical complication rates according to Clavien-Dindo surgical classification.

Quality of life as measured by EORTC Quality of Life Questionnaire-core 30 (QLQ C30). The QLQ-C30 is scored on 4 point Likert-scales: "Not at all", "A little", "Quite a bit", and "Very much." and is composed of both multi-item scales and single-item measures. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.

Quality of life as measured by the Melanoma Subscale and Melanoma Surgery Subscale of Functional Assessment of Cancer Therapy - Melanoma (FACT-M). The FACT-M is scored on a 5 point Likert-scale: "Not at all", "A little bit", "Somewhat", "Quite a bit", and "Very much.". A Higher score represents higher Health Related Quality of Life (HRQoL).

Quality of life as measured by the Cancer Worry Scale. The Cancer Worry Scale is scored on a 4 point Likert-scale: "Almost never", "Sometimes", "Often", and "Almost always". Higher scores indicate more worrying about cancer.

Quality of life as measured by the Hospital Anxiety and Depression Scale (HADS) questionnaire. The HADS is a questionnaire that is scored on several 4 point Likert-scales. Higher score on the HADS questionnaire indicates more hospital-related anxiety and depression.

Quality of life as measured by the 5-level EuroQOL-5D questionnaire (EQ-5D-5L).

Quality of life as measured by an immunotherapy-specific questionnaire.

Quality of life as measured by an assessment of work performance.

Quality of life as measured by a questionnaire on sexual health.

Quality of life as measured by the Amsterdam Cognition Scale.

Cost-effectiveness measured by an incremental cost-effectiveness ratio (ICER) (e.g., incremental cost per quality-adjusted life-year (QALY) gained).

Glioblastoma

Astrocytoma

Antirheumatic Agents

Cyclophosphamide

All patients receive depletion of regulatory T cells, reoperation, followed by a personalized cancer vaccine and double checkpoint blockade.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Relatlimab With Nivolumab and 5-Azacytidine for the Treatment of AML	NCT04913922	Acute Myeloid L...	Azacitidine Inj... Nivolumab Relatlimab	18 Years -	Ludwig-Maximilians - University of Munich
rHSC-DIPGVax Plus Checkpoint Blockade for the Treatment of Newly Diagnosed DIPG and DMG	NCT04943848	Diffuse Intrins... Diffuse Midline...	rHSC-DIPGVax Balstilimab Zalifrelimab	12 Months - 18 Years	Ann & Robert H Lurie Children's Hospital of Chicago
Relatlimab With Nivolumab and 5-Azacytidine for the Treatment of AML	NCT04913922	Acute Myeloid L...	Azacitidine Inj... Nivolumab Relatlimab	18 Years -	Ludwig-Maximilians - University of Munich
Neoadjuvant Study With Combination Immuno-oncology for Primary Clear Cell Renal Cell Cancer	NCT05148546	Renal Cell Carc...	Neoadjuvant niv... Neoadjuvant ipi... Neoadjuvant rel...	18 Years -	The Netherlands Cancer Institute
Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma	NCT04949113	Malignant Melan...	Neoadjuvant ipi... Adjuvant nivolu...	16 Years -	The Netherlands Cancer Institute
Autologous Dendritic Cells, Metronomic Cyclophosphamide and Checkpoint Blockade in Children With Relapsed HGG	NCT03879512	Childhood Gliob...	depletion of re... reoperation cancer vaccine checkpoint bloc...	3 Years - 21 Years	Wuerzburg University Hospital
Pembrolizumab With Sitravatinib in Recurrent Endometrial Cancer and Other Solid Tumors With Deficient Mismatch Repair System	NCT05419817	Recurrent Endom... Solid Tumors	pembrolizumab Sitravatinib	18 Years -	University of Pittsburgh
Neoadjuvant Study With Combination Immuno-oncology for Primary Clear Cell Renal Cell Cancer	NCT05148546	Renal Cell Carc...	Neoadjuvant niv... Neoadjuvant ipi... Neoadjuvant rel...	18 Years -	The Netherlands Cancer Institute
Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma	NCT04949113	Malignant Melan...	Neoadjuvant ipi... Adjuvant nivolu...	16 Years -	The Netherlands Cancer Institute

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