Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Sarcoma

Osteosarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Soft Tissue Sarcoma

Micronutrients

All Drugs and Chemicals

Antineoplastic Agents

Vitamins

Ascorbic Acid

Gemcitabine

Antimetabolites

Vitamin C

The study will begin with a safety run-in.

A patient-individualized pharmacokinetically-guided dose escalation design will be used for Ascorbate. Gemcitabine is administered following standard fixed dose infusion practice adopted at The University of Iowa Hospitals \& Clinics. Ascorbate is infused prior to gemcitabine. Cycles are 28 days. Patients will be treated for a total of 6 cycles and assessed every 2 cycles for disease response.

A patient-individualized pharmacokinetically-guided dose escalation design will be used for Ascorbate. The goal of the within-patient dose escalation is to achieve a target plasma ascorbate level between 20mM and 30mM. The administered dose levels under consideration are listed below.

Dose Level Ascorbate

* 2 60 g/m2 IV Days (1,2,8,9,15,16)
* 1 50 g/m2 IV Days (1,2,8,9,15,16) 0 (Starting dose) 40 g/m2 IV Days (1,2,8,9,15,16)

  * 1 30 g/m2 IV Days (1,2,8,9,15,16)

Ascorbate

Gemcitabine 900 mg/m2 given at a fixed dose rate of 10 mg/m2/min on D1, D8 and D15 to be given over 90 min every 28 days

David Dickens, MD, FAAP

The purpose of this research study is to see if a high dose of ascorbate (Vitamin C), in combination with the chemotherapy drug gemcitabine, is safe and effective in adolescents with locally advanced unresectable or metastatic soft tissue and bone sarcomas

The primary objective of the expansion cohort of this pilot study is to evaluate preliminary evidence of anti-tumor activity of intravenous ascorbate in combination with gemcitabine as assessed by overall response rate to inform a subsequent Phase II trial.

Gemcitabine With Ascorbate Including Adolescents

A Pilot Study of Gemcitabine Plus High-Dose Ascorbate in Locally Advanced Unresectable or Metastatic Soft Tissue and Bone Sarcomas Including Adolescents

Occurrence of adverse events as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The number and severity of all adverse events will be summarized by simple descriptive statistics.

Overall Response Rate (ORR) as defined by the percentage of patients with a complete or partial response, according to RECIST 1.1 guidelines

Progression Free Survival (PFS) defined as the time from first day of study treatment to the first documented disease progression or death due to any cause, RECIST 1.1 guidelines

Overall Survival (OS) defined as the time from first day of study treatment to death due to any cause

David Dickens

Clinical Professor

Digestive System Diseases

Liposarcoma

Gastrointestinal Stromal Tumors

Histiocytoma, Malignant Fibrous

Histiocytoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Neoplasms, Adipose Tissue

Neoplasms, Fibrous Tissue

Undifferentiated Pleomorphic Sarcoma

Nivolumab

Antibodies

Antibodies, Monoclonal

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress after 10 weeks on single agent nivolumab may elect to cross over to Arm II.

Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress by imaging during the first 12 weeks of therapy may continue treatment, at the discretion of the patient and treating investigator.

Laboratory Biomarker Analysis

Quality-of-Life Assessment

Sandra P D'Angelo

This randomized phase II trial studies how well nivolumab with or without ipilimumab works in treating patients with sarcoma that has spread from the primary site to other parts of the body (metastatic) or cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether nivolumab works better with or without ipilimumab in treating patients with metastatic or unresectable sarcoma.

PRIMARY OBJECTIVE:

I. To evaluate the confirmed response rate of single agent nivolumab and dual agent nivolumab plus ipilimumab in patients with locally advanced/unresectable or metastatic soft tissue sarcoma.

SECONDARY OBJECTIVES:

I. To evaluate adverse event rates (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\]4.0) within each treatment arm.

II. To evaluate duration of response, clinical benefit rate, time to progression, progression-free survival, and overall survival within each treatment arm.

CORRELATIVE SCIENCE OBJECTIVES:

I. To potentially detect an early signal of confirmed response rate within a histologically defined patient cohort.

II. To assess the potential association between programmed cell death 1 ligand 1 (PD-L1) expression (by immunohistochemistry \[IHC\]) and clinical outcome, within each treatment.

III. To evaluate associations between selected biomarker measured in serial peripheral blood and with clinical efficacy, within each treatment.

IV. To evaluate the association between selected biomarker measured in tumor tissue with clinical efficacy, within each treatment.

V. To evaluate the association between baseline tumor mutational burden and neoantigen production with clinical efficacy within each treatment.

EXPLORATORY PHASE II OBJECTIVES (CROSSOVER TREATMENT):

I. To evaluate secondary endpoints within patients crossing over to dual agent nivolumab plus ipilimumab after experiencing progressive disease while receiving single agent nivolumab.

II. To evaluate correlative science objectives endpoints within patients crossing over to dual agent nivolumab plus ipilimumab after experiencing progressive disease while receiving single agent nivolumab.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress after 10 weeks on single agent nivolumab may elect to cross over to Arm II.

ARM II: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress by imaging during the first 12 weeks of therapy may continue treatment, at the discretion of the patient and treating investigator.

After completion of study treatment, patients are followed up at 4 weeks and then every 6 months 3 years.

Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Sarcoma That Cannot Be Removed by Surgery

Randomized Phase II Study of Nivolumab With or Without Ipilimumab in Patients With Metastatic or Unresectable Sarcoma

Categorical data analysis and logistic regression will be used to evaluate the associations between PD-L1 expression (by IHC) and clinical outcome (e.g., response, clinical benefit, progression-free survival, and survival). Kaplan-Meier methodology and Cox proportional hazards models will be used to evaluate time to event endpoints.

Summary statistics will be used to for describing changes across time. The time course of biomarker outcomes will be investigated graphically, by summary plots or individual patient plots. If there is suggestion of meaningful trend, methods such as linear mixed models may be used to characterize the pattern of change over time. Kaplan-Meier methodology and Cox proportional hazards models will be used to evaluate time to event endpoints.

Categorical data analysis and logistic regression will be used to correlated biomarkers with and clinical outcome (e.g., response, clinical benefit, time to progression, progression free survival, and survival) within each study component. Kaplan-Meier methodology and Cox proportional hazards models will be used to evaluate time to event endpoints.

Confirmed response will be evaluated in patients who crossover from single agent nivolumab to dual agent treatment following progression.

Evaluated using Kaplan-Meier methodology.

The number of participants who achieved a confirmed response is defined as the number of patients having a best objective tumor status of complete response (CR) or partial response (PR) lasting at least 4 weeks as determined using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites).

The number of participants who experienced at least one grade 3 or higher adverse event (AE) regardless of attribution. AEs are graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5.0 beginning April 1, 2018).

Duration of response is defined for all evaluable patients who have achieved a confirmed response as the date at which the patient's objective status is first noted to be a CR or PR to the earliest date progression (PD) is documented. The distribution of duration of response will be estimated using the method of Kaplan-Meier. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites, PD: Any new lesion or increase by \>= 50% of previously involved sites from nadir).

The 6-month clinical benefit rate is defined as the percentage of participants with a response or stable disease (CR, PR, or SD) at 6 months. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites, PD: Any new lesion or increase by \>= 50% of previously involved sites from nadir, SD: Not CR/PR or PD).

Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression (PD) is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. (PD: Any new lesion or increase by \>= 50% of previously involved sites from nadir).

Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

National Cancer Institute (NCI)

Serious AEs and Other (Not Including Serious) AEs summary tables summarizes AEs assessed for participants who started treatment and were evaluable for AEs. All-cause mortality is assessed for all enrolled participants. Adverse events are described and graded using the terminology and grading categories defined in the NCI's Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. However, CTCAE v5.0 is used for serious AE reporting through CTEP-AERS as of April 1, 2018.

Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity.

Initial Single

Patients receive 3mg/kg nivolumab IV over 30 minutes and 1mg/kg ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive 3mg/kg nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity.

Initial Dual

Dedifferentiated liposarcoma (LPS) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity.

LPS Single

Dedifferentiated liposarcoma (LPS) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes and 1mg/kg ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive 3mg/kg nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress by imaging during the first 12 weeks of therapy may continue treatment, at the discretion of the patient and treating investigator.

LPS Dual

Undifferentiated Pleomorphic Sarcoma \& Malignant Fibrous Histiocytoma (UPS/MFH) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity.

UPS/MFH Single

Undifferentiated Pleomorphic Sarcoma \& Malignant Fibrous Histiocytoma (UPS/MFH) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes and 1mg/kg ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive 3mg/kg nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress by imaging during the first 12 weeks of therapy may continue treatment, at the discretion of the patient and treating investigator.

UPS/MFH Dual

Gastrointestinal stromal tumor (GIST) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity.

GIST Single

Gastrointestinal stromal tumor (GIST) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes and 1mg/kg ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive 3mg/kg nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress by imaging during the first 12 weeks of therapy may continue treatment, at the discretion of the patient and treating investigator.

GIST Dual

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Eastern Cooperative Oncology Group PS Scale: 0)Fully active, able to carry on all pre-disease performance without restriction; 1)Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2)Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3)Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4)Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.

ECOG Performance Status

Randomized patients are included in this analysis.

Sandra P. D'Angelo, M.D.

Participants who completed the study and were evaluable for the primary endpoint are included in this analysis.

Number of Participants Who Achieved a Confirmed Response

Grade 3 Event

Grade 4 Event

Grade 5 Event

Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress on single agent nivolumab may elect to cross over to Initial Cohort - Arm II.

Randomized patients who received treatment (i.e. exclude cancel patients).

Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Event Regardless of Attribution

Participants who achieved a confirmed response are included in this analysis.

Duration of Response

Randomized Initial Cohort participants who received treatment (i.e. exclude cancel patients) Only.

6-Month Clinical Benefit Rate [Initial Cohort]

Randomized Expansion LPS and UPS/MFH Cohorts Participants who received treatment Only

6-Month Clinical Benefit Rate [Expansion LPS and UPS/MFH Cohorts Only]

Randomized Expansion GIST Cohort Participants who received treatment Only.

6-Month Clinical Benefit Rate [Expansion GIST Cohort Only]

Progression-free Survival (PFS)

Overall Survival (OS)

PD-L1 Expression Assessed Using Immunohistochemistry (IHC)

Change in Selected Biomarkers Measured in Serial Peripheral Blood

Selected Biomarkers Measured in Tumor Tissue

Confirmed Response in Patients Who Crossover From Single Agent Nivolumab to Dual Agent Treatment Following Progression

Duration of Response in Patients Who Crossover From Single Agent Nivolumab to Dual Agent Treatment Following Progression

PFS in Patients Who Crossover From Single Agent Nivolumab to Dual Agent Treatment Following Progression

OS in Patients Who Crossover From Single Agent Nivolumab to Dual Agent Treatment Following Progression

Initial Cohort - Arm I (Nivolumab)

Initial Cohort - Arm II (Nivolumab, Ipilimumab)

Dedifferentiated liposarcoma (LPS) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress after 10 weeks on single agent nivolumab may elect to cross over to LPS Cohort - Arm II.

Expansion LPS Cohort - Arm I (Nivolumab)

Expansion LPS Cohort - Arm II (Nivolumab, Ipilimumab)

Undifferentiated Pleomorphic Sarcoma \& Malignant Fibrous Histiocytoma (UPS/MFH) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress after 10 weeks on single agent nivolumab may elect to cross over to UPS/MFH Cohort - Arm II.

Expansion UPS/MFH Cohort - Arm I (Nivolumab)

Expansion UPS/MFH Cohort - Arm II (Nivolumab, Ipilimumab)

Gastrointestinal stromal tumor (GIST) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress after 10 weeks on single agent nivolumab may elect to cross over to GIST Cohort - Arm II.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Gemcitabine With Ascorbate Including Adolescents	NCT04877587	Soft Tissue Sar... Bone Sarcoma Unresectable So... Metastatic Bone... Metastatic Soft... Unresectable Bo...	Ascorbate Gemcitabine	13 Years - 17 Years	University of Iowa
Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Sarcoma That Cannot Be Removed by Surgery	NCT02500797	Locally Advance... Locally Advance... Locally Advance... Locally Advance... Metastatic Bone... Metastatic Lipo... Metastatic Soft... Metastatic Undi... Metastatic Unre... Pleomorphic Lip... Stage III Bone ... Stage III Soft ... Stage IV Bone S... Stage IV Soft T... Stage IVA Bone ... Stage IVB Bone ... Unresectable Bo... Unresectable De... Unresectable Li... Unresectable Ma... Unresectable So...	Ipilimumab Laboratory Biom... Nivolumab Quality-of-Life...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for unresectable bone sarcoma