Neoplasms

All Conditions

Rare Diseases

Sarcoma

Sarcoma, Alveolar Soft Part

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Soft Tissue Sarcoma

Alveolar Soft Part Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Atezolizumab

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Immunologic Factors

Patients receive atezolizumab IV over 30-60 minutes on day 8 of cycle 1, and then on day 1 of subsequent cycles. Patients also receive selinexor PO QW on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy at baseline, cycle 1 day 8 and cycle 3 day 1, CT and MRI at baseline, end of cycle 2, and every 2 cycles thereafter, and collection of blood samples throughout the study.

Patients receive atezolizumab IV over 30-60 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Arm I. Patients also undergo biopsy at baseline and cycle 3 day 1, CT and MRI at baseline, end of cycle 2, and every 2 cycles thereafter, and collection of blood samples throughout the study.

Biopsy

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Selinexor

Site Public Contact

James S. Hu

Sosipatros A. Boikos

A P. Chen

Minh Phan

Melissa A. Burgess

Anthony P. Conley

Alice P Chen

This phase II trial tests whether atezolizumab alone or in combination with selinexor works to shrink tumors in patients with alveolar soft part sarcoma and whether the study drugs are better than the usual approach in treating this type of cancer. The usual approach is defined as care most people get for alveolar soft part sarcoma if they are not part of a clinical study, which includes treatment with radiation, kinase inhibitor drugs, immunotherapy drugs, or chemotherapy drugs. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Selinexor is in a class of medications called selective inhibitors of nuclear export (SINE). It works by blocking a protein called CRM1, which may help keep cancer cells from growing and may kill them. Giving atezolizumab alone or in combination with selinexor may help shrink tumors and stabilize the cancer in patients with alveolar soft part sarcoma.

PRIMARY OBJECTIVE:

I. Determine the overall response rate (by Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\]1.1) for selinexor in combination with atezolizumab in immune checkpoint inhibitor (ICI)-naive patients with alveolar soft part sarcoma (ASPS).

SECONDARY OBJECTIVE:

I. Assess the number of activated CD8+ T cells infiltrating the tumor before and after atezolizumab + selinexor combination treatment, and correlate treatment-induced changes with clinical response.

EXPLORATORY OBJECTIVES:

I. Compare RECIST v 1.1 versus (vs) immune RECIST (iRECIST) in patients with ASPS on atezolizumab + selinexor.

II. Examine changes in PD-1/PD-L1 expression in the tumor microenvironment before and after atezolizumab + selinexor treatment, and correlate treatment-induced changes with clinical response.

III. Evaluate potential associations between atezolizumab + selinexor activity and tumor genomic alterations.

OUTLINE: This is a randomized phase 2 trial that incorporates a safety run-in of the selinexor in combination with atexolizumab. After the safety run-in phase, patients are randomized to 1 of 2 arms. Patients with advanced soft tissue sarcoma are assigned to Arm I.

ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 8 of cycle 1, and then on day 1 of subsequent cycles. Patients also receive selinexor orally (PO) once weekly (QW) on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy at baseline, cycle 1 day 8 and cycle 3 day 1, computed tomography (CT) and magnetic resonance imaging (MRI) at baseline, end of cycle 2, and every 2 cycles thereafter, and collection of blood samples throughout the study.

ARM II: Patients receive atezolizumab IV over 30-60 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Arm I. Patients also undergo biopsy at baseline and cycle 3 day 1, CT and MRI at baseline, end of cycle 2, and every 2 cycles thereafter, and collection of blood samples throughout the study.

After completion of study treatment, participants are followed up for 30 days.

Testing Atezolizumab With or Without Selinexor in Patients >= 18 Years Old With Alveolar Soft Part Sarcoma, the Axiom Study

A Randomized Phase 2 Study of Atezolizumab With or Without Selinexor in Alveolar Soft Part Sarcoma (AXIOM)

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Defined by Response Evaluation Criteria in Solid Tumors version 1.1, and calculated using a two-sample test of proportions (normal approximation) with one-sided type-I error 0.1.

Defined as minimum of 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including baseline) AND an absolute increase of \>= 5 mm. Appearance of new lesions will also constitute PD (including lesions in previously unassessed areas).

National Cancer Institute (NCI)

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Skin and Connective Tissue Diseases

Carcinoma, Non-Small-Cell Lung

Carcinoma

Lung Neoplasms

Small Cell Lung Carcinoma

Carcinoma, Hepatocellular

Melanoma

Neoplasms, Glandular and Epithelial

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Small Cell Lung Cancer

Neuroendocrine Tumor

Neuroepithelioma

Immunomodulating Agents

Atezolizumab administered via IV at either 1,200 mg q3 weeks, or 1,680 mg q4 weeks for the first 2 doses followed by 850mg q2 weeks or q6 weeks.

NCI Medical Oncology Referral Office

James L Gulley, M.D.

National Cancer Institute Referral Office

Background:

A type of drug called monoclonal antibody immune checkpoint inhibitors are often used in cancer treatment. These drugs help the body s immune system fight cancer by blocking proteins that cause cancer cells to grow. One of these drugs (atezolizumab) is approved to treat certain cancers. Researchers want to find out if lower doses of this drug might provide the same benefit with fewer adverse effects.

Objective:

To test different doses and timing of atezolizumab for people with cancer.

Eligibility:

People aged 18 years and older with cancer that has spread locally or to other organs. They must be eligible for treatment with the study drug.

Design:

Participants will be screened. They will have blood tests and imaging scans. They will provide a sample of tissue from their tumor.

Atezolizumab is administered through a tube attached to a needle inserted into a vein in the arm. Participants will take this drug alone or combined with other drugs prescribed for their care.

The first 2 treatments will be done per the FDA recommended dose and schedule. Before administering the second dose of the study drug, researchers will check the level of the drug in the participant s blood. Depending on those results, their 3rd dose will be scheduled 2 to 6 weeks later.

For the 3rd dose of the study drug, participants will switch to the FDA minimum dosage. Dosages of any other drugs will not change.

Researchers will continue to test the levels of the drug in participants blood before each treatment for 16 weeks. After that, these levels will be tested every 3 months.

Study treatment may last up to 2 years.

Background:

* The treatment of many cancers has been revolutionized through the use of monoclonal antibody immune checkpoint inhibitor drugs, particularly those that block the interaction of the anti-programmed death-ligand 1 (PD-L1) with the programmed death-1 (PD-1) receptor.
* Atezolizumab was initially tested in a phase 1a multicenter, dose-escalation, and dose- expansion study (NCT01375842) which showed that the drug was well tolerated and produced clinical responses in a variety of tumors.
* The initially approved atezolizumab regimen was 1,200 mg every 3 weeks, but 840 mg every 2 weeks was added based on the data from the TNBC trial (NCT01375842). This was taken further by Morrissey et al., who used population pharmacokinetic (PK) simulations to determine that dosing regimens of 840 mg every 2 weeks and 1,680 mg every 4 weeks are interchangeable with 1,200 every 3 weeks in terms of efficacy, leading the Food and Drug Administration (FDA) to expand the dosing regimens for atezolizumab.
* The standard dosing regimens yield steady-state concentrations greater than 10-fold above the stated minimum effective concentration of 6 g/mL, to ensure adequate exposure for all patients, including patients that may experience lower exposure due to the incidence of anti-drug-antibodies (ADA). Atezolizumab exhibits a flat exposure- response relationship.

Objective:

-To test the feasibility of reducing drug exposure while maintaining plasma drug concentration at or above the expected target trough value during a 16-week study period by using a method for therapeutic drug monitoring of atezolizumab.

Eligibility:

* Age \>= 18 years old.
* Participants with a locally advanced or metastatic cancer who are candidates for treatment with atezolizumab, either alone or in combination with other FDA-approved drug(s).
* Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-2.
* Adequate organ and marrow function.

Design:

* This is a phase I feasibility study of a therapeutic drug monitoring (TDM)-based method for atezolizumab dosing.
* The participants will start with FDA approved dose and frequency of atezolizumab (840 mg every 2 weeks, 1,200 mg every 3 weeks, or 1,680 mg every 4 weeks) selected by their treating physician for the first two doses of the drug per standard of care.
* After the second dose, starting at 3rd dose, the dose of the drug will be switched to 840 mg and will be used going forward in the trial in all participants.
* Prior to each dose, starting at the 2nd dose, a trough will be drawn which will be by the population PK model to predict the timing of the next dose to maintain the atezolizumab target trough for each participant specifically. This will be repeated for the first 16 weeks of treatment.
* After 16 weeks of treatment, the timing of the next dose to maintain the atezolizumab target trough for each participant will be monitored and adjusted (if necessary) every 3 months for each participant until 2 years.

A Study of Therapeutic Drug Monitoring-Based Atezolizumab Dosing

A Feasibility Multicenter Phase I Study of Therapeutic Drug Monitoring-Based Atezolizumab Dosing

The fraction of participants that can be dosed with 840mg of atezolizumab at less frequent intervals while maintaining a trough PK concentration at or above 6 mg/mL

PK evaluations before every atezolizumab infusion starting from the second dose until 16 weeks after atezolizumab treatment and every 3 months after 16 weeks on treatment.

Pazopanib 800mg po qd until disease progression

Pazopanib 800mg qd daily for 4 weeks = 1 cycle

Pazopanib

Alveolar soft part sarcoma (ASPS), a rare subset of STS (\<1%) harbors t(X;17)(p11;q25) translocation and produces resultant ASPL-TFE3 fusion protein. Due to its nature of high expression of angiogenic factors, sunitinib and cediranib produced overall response rates of 55% and 43%, respectively. However, the efficacy of pazopanib is unknown in metastatic ASPS.

Pazopanib, a multi-targeted anti-angiogenesis inhibitor significantly prolonged progression-free survival (PFS) in patients with metastatic soft-tissue sarcoma (STS) after failure to anthracycline-based regimen (pazopanib vs placebo, 4.6 vs 1.6 months, HR=0.31, 95% CI 0.24-0.40; P \< .0001). Regarding sunitinib (continuous daily dose of 37.5mg), after a median duration of 10 months, median OS and PFS were 19 months and 17 months, respectively in a small retrospective study (ASPS, N=9). With regard to cediranib, 6-month PFS was over 60%. In addition, randomized phase II trial of sunitinib vs cediranib with cross-over at disease progression was recently initiated (NCT01391962). However, the efficacy of pazopanib is unknown in metastatic ASPS.

Pazopanib for Metastatic Alveolar Soft Part Sarcoma

A Phase II Trial of Pazopanib in Patients With Metastatic Alveolar Soft Part Sarcoma

Seoul National University Bundang Hospital

Asan Medical Center

Samsung Medical Center

Severance Hospital

Seoul National University Hospital

MD, PhD

Bevacizumab

Immunoglobulin G

Endothelial Growth Factors

Mitogens

Immunoglobulins, Intravenous

Angiogenesis Inhibitors

Growth Inhibitors

Patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT imaging, and collection of blood and urine at baseline.

Patients receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT imaging, and collection of blood and urine at baseline.

This phase II trial studies how well atezolizumab or atezolizumab plus bevacizumab works in treating patients with alveolar soft part sarcoma that has not been treated, has spread from where it started to other places in the body (advanced) and cannot be removed by surgery (unresectable). Atezolizumab works by unblocking the immune system, allowing the immune system cells to recognize and then attack tumor cells. Bevacizumab works by controlling the growth of new blood vessels. Giving atezolizumab alone or atezolizumab with bevacizumab may shrink the cancer.

PRIMARY OBJECTIVES:

I. Determine the objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 of atezolizumab in patients with advanced alveolar soft part sarcoma (ASPS) in adult subjects \>= 18 years and in pediatric/adolescent subjects \>= 2 years.

II. Determine the ORR using RECIST v 1.1 of atezolizumab and bevacizumab in subjects \>= 18 years old with advanced ASPS that has progressed on atezolizumab monotherapy.

SECONDARY OBJECTIVES:

I. Determine duration of response (DOR) to atezolizumab monotherapy or atezolizumab plus bevacizumab using RECIST v 1.1 and/or change in clinical symptoms.

II. Measure progression-free survival (PFS) time for patients receiving atezolizumab monotherapy or atezolizumab plus bevacizumab as determined by investigator using RECIST v 1.1.

III. Assess the number of activated CD8+ T cells infiltrating the tumor before and after treatment with atezolizumab monotherapy or atezolizumab plus bevacizumab, and correlate treatment-induced changes with clinical response.

IV. Measure and describe the atezolizumab pharmacokinetics (PK) and anti-drug antibodies (ADA) in patients ages 2-11 years old.

EXPLORATORY OBJECTIVES:

I. Compare RECIST v 1.1 vs immune RECIST (iRECIST) in patients with ASPS on atezolizumab and atezolizumab + bevacizumab.

II. Assess the post-progression response rate among patients who progress while on treatment holiday and then resume treatment.

III. Analyze the genomic and immune profiles of tumors expressing type 1 or type 2 ASPL-TFE3 fusions and correlate findings with response to atezolizumab or atezolizumab in combination with bevacizumab.

IV. Measure and describe the atezolizumab pharmacokinetics (PK) in patients \>= 12 years old.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients in arm I who do achieve disease progression may cross-over to arm II. Patients also undergo computed tomography (CT) imaging, and collection of blood and urine at baseline.

ARM II: Patients receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT imaging, and collection of blood and urine at baseline.

After completion of study treatment, patients are followed up for 27-30 days. Patients who are progression-free at the end of a 2-year treatment holiday are followed every 6 months.

Testing Atezolizumab Alone or Atezolizumab Plus Bevacizumab in People With Advanced Alveolar Soft Part Sarcoma

A Phase 2 Study of Anti-PD-L1 Antibody (Atezolizumab) in Alveolar Soft Part Sarcoma

Will be evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. If at least 3 responses (at least 12.5%) are observed among the 24 evaluable patients, this regimen would be considered worthy of further testing in this disease.

Will be assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Exploratory evaluations will be performed, with results reported with appropriate caveats about the exploratory nature of the analysis, and without formal adjustment for multiple comparisons.

Will be evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. Exploratory evaluations will be performed, with results reported with appropriate caveats about the exploratory nature of the analysis, and without formal adjustment for multiple comparisons.

Response will be correlated with expression of potential immune biomarkers in paired biopsies. Exploratory evaluations will be performed, with results reported with appropriate caveats about the exploratory nature of the analysis, and without formal adjustment for multiple comparisons.

Will be evaluated by immune Response Evaluation Criteria in Solid Tumors. Response evaluated with immune Response Evaluation Criteria in Solid Tumors version 1.1 will be compared to immune Response Evaluation Criteria in Solid Tumors. Exploratory evaluations will be performed, with results reported with appropriate caveats about the exploratory nature of the analysis, and without formal adjustment for multiple comparisons.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Testing Atezolizumab With or Without Selinexor in Patients >= 18 Years Old With Alveolar Soft Part Sarcoma, the Axiom Study	NCT05333458	Advanced Alveol... Advanced Soft T... Metastatic Alve... Unresectable Al...	Atezolizumab Biopsy Biospecimen Col... Computed Tomogr... Magnetic Resona... Selinexor	18 Years -	National Cancer Institute (NCI)
A Study of Therapeutic Drug Monitoring-Based Atezolizumab Dosing	NCT06066138	Locally Advance... Metastatic Alve... Locally Advance... Metastatic Non ... Locally Advance... Metastatic Smal... Locally Advance... Metastatic Hepa... Locally Advance... Metastatic Mela...	Atezolizumab	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
A Study of Therapeutic Drug Monitoring-Based Atezolizumab Dosing	NCT06066138	Locally Advance... Metastatic Alve... Locally Advance... Metastatic Non ... Locally Advance... Metastatic Smal... Locally Advance... Metastatic Hepa... Locally Advance... Metastatic Mela...	Atezolizumab	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Pazopanib for Metastatic Alveolar Soft Part Sarcoma	NCT02113826	Metastatic Alve...	Pazopanib	18 Years -	Seoul National University Hospital
Testing Atezolizumab With or Without Selinexor in Patients >= 18 Years Old With Alveolar Soft Part Sarcoma, the Axiom Study	NCT05333458	Advanced Alveol... Advanced Soft T... Metastatic Alve... Unresectable Al...	Atezolizumab Biopsy Biospecimen Col... Computed Tomogr... Magnetic Resona... Selinexor	18 Years -	National Cancer Institute (NCI)
A Study of Therapeutic Drug Monitoring-Based Atezolizumab Dosing	NCT06066138	Locally Advance... Metastatic Alve... Locally Advance... Metastatic Non ... Locally Advance... Metastatic Smal... Locally Advance... Metastatic Hepa... Locally Advance... Metastatic Mela...	Atezolizumab	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Testing Atezolizumab Alone or Atezolizumab Plus Bevacizumab in People With Advanced Alveolar Soft Part Sarcoma	NCT03141684	Metastatic Alve... Unresectable Al...	Atezolizumab Bevacizumab Biospecimen Col... Computed Tomogr...	2 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for metastatic alveolar soft part sarcoma