Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Neoplasm Metastasis

Pleural Effusion, Malignant

Pleural Effusion

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

All Drugs and Chemicals

Antineoplastic Agents

Analgesics

Immunomodulating Agents

Interleukin-2

After local irradiation (5 x 4 Gy) given over 5 consecutive days and 2 treatment free days cohorts of 3-6 subjects will receive EMD 521873 (as a 1h-infusion) on 3 consecutive days in 3-week cycles at dose levels of 0.15, 0.30, and 0.45 mg/kg, respectively.

EMD 521873

Sonia Quaratino, MD, PhD

Primary trial objective in this single arm trial is to assess the safety and tolerability of Selectikine (EMD 521873) given in combination with and local tumor irradiation and to determine whether the maximum tolerated dose (MTD) is reached with EMD 521873 doses of up to 0.45 mg/kg.

Secondary objectives are to evaluate PK, immunogenicity, overall response, changes in tumor marker levels and circulating tumor cell numbers, progression-free survival and overall survival. Also, to evaluate biological/immune responses to EMD 521873.

NSCLC patients have to be stable (PR or SD) after first-line chemotherapy in order to be enrolled. A total of 12 to 24 patients are planned. Patients will remain on the dose throughout the trial. It is intended to administer at least 4 cycles (21 d each), or until progression or 2nd line therapy becomes necessary.

EMD 521873 Plus Radiotherapy in Non Small Cell Lung Cancer (NSCLC)

An Open-label, Phase Ib, Dose-escalation Trial on the Safety, Tolerability, Pharmacokinetics, Immunogenicity, Biological Effects and Antitumor Activity of EMD 521873 in Combination With Local Irradiation (20 Gy) of Primary Tumors or Metastases in Subjects With Non-small Cell Lung Cancer Stage IIIb With Malignant Pleural Effusion or Stage IV With Disease Control (Partial Response or Stable Disease) After Application of 4 Cycles of Platinum-based, First-line Chemotherapy

Merck KGaA, Darmstadt, Germany

Dose escalation: GI-102, multiple ascending doses

Dose escalation phase:

GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 cycles).

GI-102

Dose expansion phase:

GI-102 will be administered via IV infusion Q3W up to 2 years (approximately 35 cycles).

Jay Kim

Woosun Lee

Mahesh Seetharam

Yujie Zhao

Jian Li Campian, PhD.

Wen Wee Ma, M.B.B.S

Seock-Ah Im, M.D., Ph.D.

Byoung Chul Cho, M.D., Ph.D.

Jung-Yun Lee, M.D., Ph.D.

Jae Lyun Lee, M.D., Ph.D.

Jeeyun Lee, M.D., Ph.D.

Byoung Yong Shim, M.D., Ph.D.

Nari Yun, PhD

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and therapeutic activity of GI-102 as a single agent over a range of advanced and/or metastatic solid tumors.

This is a phase 1/2a, open-label, dose-escalation and expansion study to evaluate the safety, tolerability, and anti-tumor effect of GI-102 as a single agent over a range of advanced and/or metastatic solid tumors. This study is adaptive in nature. While GI-102 is being investigated as a single agent in this trial, GI-102 has the potential of being combined with other agents. Based on the data from ongoing nonclinical studies and the dose escalation phase, additional combination therapies \[GI-102 + drug(s) X\] may be proposed and added to this study protocol via an amendment.

This study will comprise two phases.

* GI-102 monotherapy dose escalation phase
* GI-102 monotherapy dose expansion phase

GI-102 is a novel bi-specific Fc fusion protein containing the CD80 ectodomain as an N-terminal moiety and an interleukin (IL)-2 variant as a C-terminal moiety configurated via a human immunoglobulin G4 (IgG4) Fc. GI-102 has unique characteristics by having bispecificity to CD80 and IL2Rβγ. The CD80 portion is responsible for targeting tumor/immune cells while blocking CTLA-4 expressed on the Treg cells. The IL-2v of GI-102 is designed to abolish IL-2Rα affinity and therefore minimize the effect on Treg while it has very outstanding effect on NK and CD8 T cell proliferation and activity through IL-2Rbr affinity.

A Study to Evaluate the Safety and Therapeutic Activity of GI-102 in Patients With Advanced Solid Tumors

An Open-label, Multicenter, Dose Escalation and Expansion Phase 1/2a Study to Evaluate the Safety, Tolerability and Pharmacokinetics, and Therapeutic Activity of GI-102 in Patients With Advanced or Metastatic Solid Tumors

Serum will be assessed for the presence of ADA and Nab based on the appropriate assay.

CD4+ T cells in peripheral blood will be assessed by flow cytometry at various time points

CD8+ T cells in peripheral blood will be assessed by flow cytometry at various time points

Treg cells in peripheral blood will be assessed by flow cytometry at various time points

A DLT is defined as a clinically significant AE (classified according to the NCI CTCAE version 5) or significant laboratory abnormality that occur during the DLT assessment periods, during dose escalation and dose expansion, and is considered by the Investigator to be related to GI-102.

An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs. All AE events will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

ORR is defined as the percentage of participants with investigator-assessed objective response of complete response (CR) or partial response (PR). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions).

DCR is defined as the percentage of patients who have achieved CR, PR and stable disease (SD), per RECIST v1.1 guideline as determined by the investigators.

DCR is defined as the time from the first occurrence of a documented objective response to the time of the first document disease progression or death from any cause, whichever occurs first, per RECIST v1.1 as determined by the investigator.

PFS is defined as the time from the first study treatment (Day 1) to the first occurrence of progression or death from any cause, whichever occurs first, per RECIST v1.1 guideline as determined by the investigator

OS is defined as the time from the first study treatment to death from any cause

Based on the concentration vs time profile by dose level

GI Innovation, Inc.

Rare Diseases

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Transitional Cell Carcinoma

Camurati-Engelmann Disease

1200 mg administered intravenous (IV) every two weeks

Bintrafusp alfa (M7824)

Andrea B Apolo, M.D.

Background:

Metastatic urothelial carcinoma is lethal and has no cure. Response rates to current treatments are modest. Researchers want to find new strategies to treat the disease. In this study, they will test a drug called Bintrafusp alfa (M7824). The drug is a new immunotherapy that blocks the pathways that cancer cells use to stop the immune system from fighting cancer.

Objective:

To learn if M7824 can help the immune system's ability to fight urothelial cancer.

Eligibility:

People age 18 and older who have urothelial cancer that has spread to other parts of their body and they have been previously treated with chemotherapy or immunotherapy

Design:

Participants will be screened with a medical history and physical exam. They will have blood and urine tests. They will have imaging scans. They will have an electrocardiogram to measure heart function. Their ability to perform their normal activities will be evaluated. They may have a tumor biopsy. They will take a pregnancy test if needed.

Participants will repeat some of the screening tests during the study.

Treatment will be given in a series of 28-day cycles. Participants will get M7824 once every 2 weeks. It is given through an intravenous infusion. For this, a small plastic tube is put into an arm vein. They will get M7824 until their disease gets worse, they have unacceptable side effects, or they decide to stop treatment.

Participants will have a follow-up visit 30 days after treatment ends. Then they will be followed every 12 weeks in the clinic or by telephone/email. Follow-up will last indefinitely.

Background:

* Metastatic urothelial carcinoma is lethal and incurable with a median overall survival of 14 months from diagnosis.
* Immune checkpoint inhibitors targeting the Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have greatly changed clinical management of metastatic urothelial carcinoma (mUC) improving survival by 3 months in the second-line setting.
* Five PD-1/PD-L1 inhibitors are Food and Drug Administration (FDA)-approved for for second-line metastatic urothelial carcinoma (mUC), two agents for first-line cisplatin-ineligible mUC. However, response rates are modest, ranging from15-20% in the second-line and 24% in the first-line cisplatin-ineligible.
* Therefore, novel strategies are needed to extend benefit of immunotherapy to the remaining approximately 75% of non-responders.
* Higher levels of transforming growth factor-beta (TGF-beta) are associated with immune escape, therapy resistance and poor outcomes in advanced malignancies. Non-responders to anti-PD-1/PD-L1 antibodies have also been found to have increased TGF-beta in the tumor microenvironment.
* Bintrafusp alfa (M7824) is a novel first-in-class bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II (TGFbetaRII), which effectively functions to sequester or "trap" all three TGF-beta isoforms. A phase I study of M7824 (NCT02517398) demonstrated a manageable safety profile and clinical efficacy among patients with heavily pre-treated advanced solid tumors.
* We hypothesize that M7824 is safe and improves outcomes in patients with checkpoint naive or refractory urothelial carcinoma.

Objectives:

-To evaluate the activity of M7824 as determined by objective response rate (ORR) in two metastatic urothelial carcinoma cohorts:

* Cohort 1: Checkpoint inhibitor naive

  * Cohort 1A: cisplatin ineligible
  * Cohort 1B: refractory post-platinum therapy
* Cohort 2: Checkpoint inhibitor previously treated patients

  * Cohort 2A: previously achieved a Complete Response (CR)/Partial Response (PR)
  * Cohort 2B: previously had Stable Disease (SD)/Progressive Disease (PD)

Eligibility:

* Patients must have a histologically confirmed diagnosis of metastatic urothelial cancer.
* Patients may have been previously treated with prior cytotoxic chemotherapy regimen or targeted agent. Patients may have received any number of prior cytotoxic agents.
* 18 years of age or older

Design:

* This is an open label, non-randomized, single arm phase II trial of M7824 in checkpoint inhibitor naive and previously treated patients with urothelial carcinoma of the bladder.
* M7824 (intravenous 1200 mg fixed dose) will be delivered every 2 weeks
* Patients will receive treatment in cycles consisting of 4 weeks.
* A maximum of 75 subjects will be enrolled in this trial.

A Phase II Study of Bintrafusp Alfa (M7824) in Checkpoint Inhibitor Naive and Refractory Subjects With Urothelial Carcinoma

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

The proportion of evaluable patients with objective response rate (ORR) defined as a partial response (PR) or complete response (CR) at the end of treatment with Bintrafusp alfa (M7824). Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Complete response is disappearance of all target lesions.

The number of participants with toxicity grade \>1 assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v5.0. Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse events.

PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1 and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study; and the appearance of one or more new lesions.

Here is the number of participants that survived.

National Cancer Institute (NCI)

Principal Investigator

Treatment with Bintrafusp alfa (M7824)

Bintrafusp alfa (M7824): 1200 mg administered intravenous (IV) every two weeks

Cohort 1B - Checkpoint Inhibitor Naïve Participants Who Are Refractory Post-platinum Therapy

Treatment with Bintrafusp alfa (M7824) Bintrafusp alfa (M7824): 1200 mg administered intravenous (IV) every two weeks

Cohort 2B - Checkpoint Inhibitor Refractory Participants With Stable Disease or Progressive Disease

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Andrea B. Apolo

Partial Response

Complete Response

Proportion of Participants With an Objective Response Rate (ORR)

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Number of Participants With Toxicity Grade >1

Number of Participants With Progression Free Survival (PFS)

Number of Participants That Survived

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Overall Study

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

B-cell Lymphoma

Participants will receive DI-Leu16-IL2 1.0 milligrams per square meter (mg/m\^2) subcutaneously (SC) for 3 consecutive days every 3 weeks (21-day cycle). Participants will continue to receive therapy through the duration of the study as long as they will have clinical benefit and will not experience any untoward side effects.

Participants will receive DI-Leu16-IL2 2.0 mg/m\^2 SC for 3 consecutive days every 3 weeks (21-day cycle). Participants will continue to receive therapy through the duration of the study as long as they will have clinical benefit and will not experience any untoward side effects.

DI-Leu16-IL2 will be administered per dose and schedule specified in the arm.

DI-Leu16-IL2

Daniel Vlock, MD

This is an open-label extension study enrolling participants experiencing clinical benefit following 6 cycles of DI-Leu16-IL2 while enrolled in the Alopexx Oncology Dose-Escalation AO-101 study (NCT01874288). Participants will be permitted to continue to receive DI-Leu16-IL2 at the same dose, schedule, and route of administration they received during Study AO-101 (Main Study). Prior pre-treatment (for example, Rituximab) will continue as before.

Open-Label Extension Study of De-immunized DI-Leu16-IL2 Immunocytokine Administered in Participants With B-cell NHL

An Open-Label Extension Study of De-immunized DI-Leu16-IL2 Immunocytokine Administered in Patients With B-cell Non-Hodgkin Lymphoma (NHL)

BOR included complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), and progressive disease (PD). CR: 1)Disappearance of all detectable clinical and radiological evidence of disease; 2)lymph nodes (LN) regressed to normal size; 3)other organs (spleen, liver, kidneys) that were enlarged before therapy must have decreased in size; 4)clear bone marrow(BM) infiltrate. CRu: must meet CR criteria 1 and 3, as well as ≥1 of following: residual LN mass \>1.5 centimeters (cm) in greatest transverse diameter; individual nodes that were previously confluent regressed by \>75% in sum of product diameters (SPD); or indeterminate BM. PR: 6 largest dominant nodes or nodal masses decreased by ≤50% in SPD; no increase in size of other nodes; liver or spleen; splenic and hepatic nodules regressed ≥50% in SPD; and no new disease. SD: less than a PR but not PD. PD: 50% increase from nadir in SPD of any abnormal node for PR or nonresponders and appearance of any new lesion.

Sum of product diameters sums the product of the 2 tumor measurements on each lesion. If only 1 measurement was available, it was used as the longest length and the product of the lengths in the sum. Baseline value is the last non-missing measurement prior to receiving study drug injection in the Main Study AO-101.

Sum of longest diameters is the sum of the longest measured length of each tumor lesion. Baseline value is the last non-missing measurement prior to receiving study drug injection in the Main Study AO-101. None of the participants were considered evaluable in 'DI-Leu16-IL2 2.0 mg/m\^2' arm for this outcome measure at the end of study, and therefore, data were not collected for that arm

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAEs were defined as AEs with onset at the time of or following the start of treatment with study drug, or AEs starting before the start of treatment but increasing in severity or relationship at the time of or following the start of treatment. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

TEAEs were defined as AEs with onset at the time of or following the start of treatment with study drug, or AEs starting before the start of treatment but increasing in severity or relationship at the time of or following the start of treatment. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Clinically significant hematology and serum chemistry abnormalities were identified at the Investigator's discretion.

Clinically significant abnormal physical exams included extremities, head, ears, eyes, nose, throat, abdomen, respiratory system, lymphatic system, and integumentary system. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Clinically significant abnormal physical exams were identified at the Investigator's discretion.

Alopexx Oncology, LLC

Safety population included all enrolled participants who received at least 1 dose of study drug.

Participants received DI-Leu16-IL2 1.0 mg/m\^2 SC for 3 consecutive days every 3 weeks (21-day cycle). Participants continued to receive therapy through the duration of the study as long as they were having clinical benefit and not experiencing any untoward side effects.

DI-Leu16-IL2 1.0 mg/m^2

Participants received DI-Leu16-IL2 2.0 mg/m\^2 SC for 3 consecutive days every 3 weeks (21-day cycle). Participants continued to receive therapy through the duration of the study as long as they were having clinical benefit and not experiencing any untoward side effects.

DI-Leu16-IL2 2.0 mg/m^2

Clinical benefit was noted before the scheduled completion of the trial, hence; the study was terminated early.

Chief Medical Officer

Number of Participants With Best Overall Response (BOR) Assessed Per International Workshop for Non-Hodgkin Lymphoma (NHL) Response Criteria

Safety population included all enrolled participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure. None of the participants were considered evaluable in 'DI-Leu16-IL2 2.0 mg/m\^2' arm for this outcome measure at the end of study, and therefore, data were not collected for that arm.

Tumor Measurement: Percent Change From Baseline in Sum of Product of Diameters at the End of Study

Safety population included all enrolled participants who received at least 1 dose of study drug. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Tumor Measurement: Percent Change From Baseline in Sum of Longest Diameters at the End of Study

Any TEAEs

SAEs

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Number of Participants With a TEAE That Was Considered Related to a Clinically Significant Hematology or Serum Chemistry Abnormality

Number of Participants With a Clinically Significant Abnormal Physical Exam

Participants received DI-Leu16-IL2 1.0 milligrams per square meter (mg/m\^2) subcutaneously (SC) for 3 consecutive days every 3 weeks (21-day cycle). Participants continued to receive therapy through the duration of the study as long as they were having clinical benefit and not experiencing any untoward side effects.

Infections

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Sarcoma

Acquired Immunodeficiency Syndrome

HIV Infections

Sarcoma, Kaposi

Neoplasms, Connective and Soft Tissue

Communicable Diseases

Herpesviridae Infections

Virus Diseases

DNA Virus Infections

Neoplasms, Vascular Tissue

Soft Tissue Sarcoma

Kaposi Sarcoma

Interleukin-12

Treatment with NHS-IL12 at de-escalating doses if necessary

Treatment with NHS-IL12 at MTD and M7824 at a fixed dose

An initial dose of 16.8 mcg/kg administered subcutaneously every 4 weeks and at an MTD dose with M7824 on day 1 of a 28-day cycle.

NHS-IL12

1200 mg administered IV every two weeks while on NHS-IL12.

M7824

Irene Ekwede, R.N.

Ramya M Ramaswami, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Kaposi sarcoma (KS) tumors grow on the skin, lymph nodes, lungs, bone, and gastrointestinal tract. KS often affects people with immune deficiencies, such as among people living with HIV or those with prior history of transplant. Researchers want to see if 2 non-chemotherapy drugs can help people with KS. NHS-IL12 triggers the immune system to fight tumors. M7824 blocks the pathways that cancer cells use to stop the immune system from fighting tumors.

Objective:

To learn if giving NHS-IL12 alone or with M7824 could help the immune system fight KS tumors.

Eligibility:

People 18 and older with KS that has been treated with chemotherapy or immunotherapy

Design:

Participants will be screened with some or all of the following:

medical history

physical exam

chest X-ray

computed tomography scan

blood and urine tests

electrocardiogram and echocardiogram

skin KS lesion biopsy

lung exam

gastrointestinal exam

All participants will get NHS-IL12 every 4 weeks for up to 96 weeks (or 24cycles). It is injected under the skin.

Some participants will also get M7824 every 2 weeks for up to 96 weeks (or 24cycles). It is given through a plastic tube that is put in an arm vein.

Participants will complete questionnaires about how KS affects their quality of life. Their KS lesions will be measured and photographed. They will repeat some of the screening tests. They will give saliva samples or additional tissue samples. They will have a lung function test. Their ability to perform their normal activities will be assessed. The treatment duration is up to 96 weeks (or 24cycles) with an option to take NHS-IL12 and/or M7824 until the KS tumors are not responding, or you develop unacceptable side effects.

Participants will have follow-up visits 7 and 30 days after treatment ends, then every 3 to 6 months for the next 18 months, then once a year for 3 years.

Background:

* Kaposi Sarcoma (KS) is a multicentric angioproliferative tumor, caused by Kaposi sarcoma-associated herpesvirus, that most frequently involves the skin, but may also involve lymph nodes, lungs, bone and gastrointestinal tract. It is most common in people with HIV but may also occur in patients without a diagnosis of HIV. Patients with HIVassociated KS have worse survival than HIV-infected patients without KS.
* As it is a relapsing and remitting condition, patients with KS often require prolonged courses of cytotoxic chemotherapy.
* KS is an immune responsive tumor as interferon-alpha, pomalidomide, and restoring Tcell function in HIV + patients treated with antiretroviral drugs can result in clinical benefit and remission of KS.
* Published Phase I/II studies by our group demonstrated that IL-12 alone and in combination with liposomal doxorubicin led to clinical responses in patients with advanced KS.
* NHS-IL12 (M9241) is an immunocytokine with affinity to both single and double stranded DNA allowing for targeting of exposed DNA, which is commonly seen in necrotic tumors. This agent is able to deliver IL-12 to the tumor microenvironment promoting local immunomodulation, that results in less systemic toxicity than IL-12 systemic administration.
* M7824 is a novel bifunctional fusion protein composed of a monoclonal antibody against human PD-L1 (avelumab) fused with the extracellular domain of human TGF-beta receptor II (TGF- RII), which functions as a TGF-beta trap .
* Anti-PD-L1 and anti-PD-1 agents have been found to be active in certain virus-induced cancers, including Kaposi sarcoma, and to be safe and active in patients with HIV infection.
* Currently, no clinical data exists for the combination of NHS-IL12 and M7824. Preclinical data suggest synergy between these agents from existing ongoing studies and the available clinical data both in KS and other tumor subtypes suggest that the combination of NHSIL12 with M7824 is likely to be well-tolerated and has scientific rationale. This combination offers a new treatment approach for patients with advanced KS who have received prior therapies.

Objectives:

-Evaluate the safety, tolerability, and activity of single agent NHS-IL12 and the combination of NHS-IL12 with M7824 in participants with advanced KS.

Eligibility:

* Age \>18 years
* Histologically confirmed Kaposi sarcoma (KS)
* KS requiring systemic therapy, with a history of prior systemic therapy
* At least five measurable cutaneous KS lesions with no previous local radiation, surgical or intralesional cytotoxic therapy to these measurable lesions.
* ECOG Performance Status (PS) less than or equal to 2
* Participant must be willing to give informed consent.
* Participants can be HIV positive or negative.
* Antiretroviral therapy (ART) for HIV+ participants for 8 or more weeks prior to entry with an HIV viral load of \<400 copies/ml and CD4+ T-cell count \>50 cells/microliter.
* Participants with bleeding from visceral sites of KS or requiring blood transfusions in the 2 weeks prior to study entry will not be eligible.

Design:

* This is a Phase I/II study assessing the safety and efficacy of NHS-IL12 alone or in combination with M7824 in participants with advanced KS. Participants will receive therapy until optimal tumor response, unacceptable toxicity, the participant s request to discontinue therapy, PI decision, up to a total of 96 weeks, or 24 cycles.
* Monotherapy: Participants will receive NHS-IL12 alone with a 3+3 design applicable to the first 3-6 participants at a starting dose of 16.8 microgram/kg on day 1 of a 28-day cycle. Two dose de-escalation levels (Dose Level -1: 12 microgram/kg or Dose Level -2: 8 microgram/kg) will be permitted if there is evidence of 2 or more dose limiting toxicities within the first 6 weeks of therapy. An expansion cohort has been planned to investigate the activity of this single agent in KS.
* Combination Therapy: The combination arm will open following accrual and completion of the DLT period for participants in the monotherapy arm. Up to 28 participants will be treated with M7824 (1200 mg IV, every 2 weeks) and NHS-IL12 (MTD dose from the monotherapy arm). The DLT period for this arm will be 6 weeks.

NHS-IL12 Monotherapy and in Combination With M7824 in Advanced Kaposi Sarcoma

Phase I/II Study of NHS-IL12 Monotherapy and in Combination With M7824 in Advanced Kaposi Sarcoma

.All IPD recorded in the medical record will be shared with intramural investigators upon request.

The fraction of participants with toxicity noted at each dose level will be reported by grade and type of toxicity identified. Maximum tolerated dose will also be reported.

duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first

Percentage of participants with the best overall response of CR or PR to therapy

the time criteria are met for CR or PR (whichever is recorded first) until the first date that participant no longer qualifies as a PR

Participants will receive DI-Leu16-IL2 0.5 mg/m\^2 subcutaneously (SC) for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

Participants will receive DI-Leu16-IL2 1.0 mg/m\^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

Participants will receive DI-Leu16-IL2 2.0 mg/m\^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

Participants will receive DI-Leu16-IL2 4.0 mg/m\^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles

Participants will receive DI-Leu16-IL2 6.0 mg/m\^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

This dose-escalation study is designed for determining the safety, tolerability, pharmacokinetics (PK), biological, and clinical activity of DI-Leu16-IL2 administered to participants with cluster of differentiation 20 (CD20) positive NHL that have failed standard rituximab-containing therapy.

The participants will be enrolled during dose escalation and during 2 expansion cohorts of up to 12 participants each.

The dose escalation portion of the trial will incorporate a modified accelerated titration design. Therefore, the trial will enroll 3 participants per dose level with a doubling of the dose at each level during the accelerated stage of the study (skipping every other dose level). Once the first instance of any Grade 3 or higher treatment related toxicity (with some notable exceptions) is observed on the first cycle, the accelerated stage will end and the trial will revert to a conventional design using cohorts of 3 or 6 participants (standard 3+3 design), with single step 2 milligrams (mg)/square meter (m\^2) increments.

To further explore the clinical efficacy, additional participants (up to 12 per cohort) may be enrolled at the optimal biologic dose (OBD) or maximum tolerated dose (MTD).

At the end of the study, participants may be enrolled into an open-label extension study (AO-101-EXT \[NCT02151903\]), at the discretion of the investigator.

A Study of De-immunized DI-Leu16-IL2 Administered Subcutaneously in Participants With B-cell NHL

A Phase I/II Study of De-immunized DI-Leu16-IL2 Immunocytokine Administered Subcutaneously in Patients With B-cell Non-Hodgkin Lymphoma (NHL)

The MTD was determined based on toxicities from the first 2 cycles of treatment. The MTD was the highest dose tested with no more than 1 participant out of 6 experienced a dose-limiting toxicity (DLT). All non-hematologic adverse events (AEs) and all hematologic AEs of greater than Grade 3 were considered relevant to determining DLTs. DLTs included absolute lymphocyte count (ALC) Grade 3 and 4 (if ALC does not resolve to baseline grade according to Common Terminology Criteria for Adverse Events (CTCAE) v4 within 5 days post the final injection per cycle of DI-Leu16-IL2), and absolute neutrophil count (ANC) Grade 3 (If ANC does not resolve to at least Grade 2 within 5 days post the final injection per cycle of DI-Leu16-IL2) and Grade 4 (any).

All non-hematologic AEs and all hematologic AEs of greater than Grade 3 were considered relevant to determining DLTs. DLTs included ALC Grade 3 and 4 (if ALC does not resolve to baseline grade according to CTCAE v4 within 5 days post the final injection per cycle of DI-Leu16-IL2), and ANC Grade 3 (If ANC does not resolve to at least Grade 2 within 5 days post the final injection per cycle of DI-Leu16-IL2) and Grade 4 (any).

BOR included complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), and progressive disease (PD). CR: 1) Disappearance of all detectable clinical and radiological evidence of disease; 2) lymph nodes (LN) regressed to normal size; 3) other organs (spleen, liver, kidneys) that were enlarged before therapy must have decreased in size; 4) clear bone marrow (BM) infiltrate. CRu: must meet CR criteria 1 and 3, as well as ≥1 of following: residual LN mass \>1.5 cm in greatest transverse diameter; individual nodes that were previously confluent regressed by \>75% in sum of product diameters (SPD); or indeterminate BM. PR: 6 largest dominant nodes or nodal masses decreased by ≤50% in SPD; no increase in size of other nodes; liver or spleen; splenic and hepatic nodules regressed ≥50% in SPD; and no new disease. SD: less than a PR but not PD. PD: 50% increase from nadir in SPD of any abnormal node for PR or nonresponders and appearance of any new lesion.

Sum of product diameters sums the product of the 2 tumor measurements on each lesion. If only 1 measurement was available, it was used as the longest length and the product of the lengths in the sum. Baseline value is the last non-missing measurement prior to receiving study drug injection. None of the participants were considered evaluable in 'DI-Leu16-IL2 0.5 mg/m\^2' arm for this outcome measure at the end of study, and therefore, data were not collected for that arm.

Sum of longest diameters is the sum of the longest measured length of each tumor lesion. Baseline value is the last non-missing measurement prior to receiving study drug injection. None of the participants were considered evaluable in 'DI-Leu16-IL2 0.5 mg/m\^2' arm for this outcome measure at the end of study, and therefore, data were not collected for that arm.

Participants received DI-Leu16-IL2 0.5 mg/m\^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

DI-Leu16-IL2 0.5 mg/m^2

Participants received DI-Leu16-IL2 1.0 mg/m\^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

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Open-Label Extension Study of De-immunized DI-Leu16-IL2 Immunocytokine Administered in Participants With B-cell NHL	NCT02151903	B-cell Non-Hodg...	DI-Leu16-IL2	18 Years -	Alopexx Oncology, LLC
A Study of De-immunized DI-Leu16-IL2 Administered Subcutaneously in Participants With B-cell NHL	NCT01874288	B-cell Non-Hodg...	DI-Leu16-IL2	18 Years -	Alopexx Oncology, LLC
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