## Protocol Section
### Identification Module
**NCT ID:** NCT06422806

**Brief Title:** Measuring if Immunotherapy Plus Chemotherapy is Better Than Chemotherapy Alone for Patients With Aggressive Poorly Differentiated Sarcomas

**Official Title:** A Randomized Phase II Trial of Doxorubicin + Pembrolizumab Versus Doxorubicin Alone for the Treatment of Undifferentiated Pleomorphic Sarcoma (UPS) and Related Poorly Differentiated Sarcomas

#### Organization Study ID Info
**ID:** NCI-2023-06412
#### Organization
**Class:** NIH
**Full Name:** National Cancer Institute (NCI)
#### Secondary ID Infos
**Domain:** CTRP (Clinical Trial Reporting Program)
**ID:** NCI-2023-06412
**Type:** REGISTRY
**Domain:** ECOG-ACRIN Cancer Research Group
**ID:** EA7222
**Type:** OTHER
**Domain:** CTEP
**ID:** EA7222
**Type:** OTHER
**ID:** U10CA180820
**Link:** https://reporter.nih.gov/quickSearch/U10CA180820
**Type:** NIH
### Status Module
#### Completion Date
**Date:** 2026-06-30

**Type:** ESTIMATED

#### Last Update Post Date
**Date:** 2024-05-21

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-18

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-06-30

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06-14

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-21
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-18
**Study First Submit QC Date:** 2024-05-18
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** NIH

**Name:** National Cancer Institute (NCI)

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Is US Export:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** This phase II trial compares the effect of immunotherapy (pembrolizumab) plus chemotherapy (doxorubicin) to chemotherapy (doxorubicin) alone in treating patients with undifferentiated pleomorphic sarcoma (UPS) or a related poorly differentiated sarcoma that has spread from where it first started to other places in the body (metastatic) or that cannot be removed by surgery (unresectable). Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's DNA and may kill tumor cells. It also blocks a certain enzyme needed for cell division and DNA repair. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Adding immunotherapy (pembrolizumab) to the standard chemotherapy (doxorubicin) may help patients with metastatic or unresectable UPS or a related poorly differentiated sarcoma live longer without having disease progression.

**Detailed Description:** PRIMARY OBJECTIVE:

I. To assess whether the combination of doxorubicin and pembrolizumab will improve progression free survival (PFS) in UPS and related poorly differentiated sarcomas relative to doxorubicin alone.

KEY SECONDARY OBJECTIVE:

I. To assess whether the combination of doxorubicin and pembrolizumab versus (vs) the re-introduction of pembrolizumab in the doxorubicin alone arm at disease progression (i.e., upfront pembrolizumab vs second line pembrolizumab) improves overall survival (OS).

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability in each treatment arm. II. To quantify overall response rate (ORR) and durability of response (DOR) in each treatment.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive doxorubicin intravenously (IV) over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients may begin receiving pembrolizumab alone IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of additional progression or unacceptable toxicity.

Patients in both arms also undergo echocardiogram (ECHO) or multigated acquisition (MUGA) scan during screening, as well as standard imaging scans and blood sample collection throughout the study.

After completion of study treatment, patients are followed up periodically for up to 5 years.

### Conditions Module

**Conditions:**

- Stage III Soft Tissue Sarcoma of the Trunk and Extremities AJCC v8

- Stage IV Soft Tissue Sarcoma of the Trunk and Extremities AJCC v8

- Undifferentiated Pleomorphic Sarcoma

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 160

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan during screening, as well as standard imaging scans and blood sample collection throughout the study.

**Intervention Names:**

- Procedure: Biospecimen Collection

- Procedure: Diagnostic Imaging

- Drug: Doxorubicin

- Procedure: Echocardiography

- Procedure: Multigated Acquisition Scan

- Biological: Pembrolizumab

**Label:** Arm A (doxorubicin and pembrolizumab

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Patients receive doxorubicin IV over 3-10 minutes or up to 3 hours on day 1 of each cycle. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients may begin receiving pembrolizumab alone IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of additional progression or unacceptable toxicity. Patients also undergo ECHO or MUGA scan during screening, as well as standard imaging scans and blood sample collection throughout the study.

**Intervention Names:**

- Procedure: Biospecimen Collection

- Procedure: Diagnostic Imaging

- Drug: Doxorubicin

- Procedure: Echocardiography

- Procedure: Multigated Acquisition Scan

**Label:** Arm B (doxorubicin)

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Arm A (doxorubicin and pembrolizumab

- Arm B (doxorubicin)

**Description:** Undergo blood sample collection

**Name:** Biospecimen Collection

**Other Names:**

- Biological Sample Collection

- Biospecimen Collected

- Specimen Collection

**Type:** PROCEDURE

#### Intervention 2

**Arm Group Labels:**

- Arm A (doxorubicin and pembrolizumab

- Arm B (doxorubicin)

**Description:** Undergo standard imaging scans

**Name:** Diagnostic Imaging

**Other Names:**

- Medical Imaging

**Type:** PROCEDURE

#### Intervention 3

**Arm Group Labels:**

- Arm A (doxorubicin and pembrolizumab

- Arm B (doxorubicin)

**Description:** Given IV

**Name:** Doxorubicin

**Other Names:**

- Adriablastin

- Hydroxydaunomycin

- Hydroxyl Daunorubicin

- Hydroxyldaunorubicin

**Type:** DRUG

#### Intervention 4

**Arm Group Labels:**

- Arm A (doxorubicin and pembrolizumab

- Arm B (doxorubicin)

**Description:** Undergo ECHO

**Name:** Echocardiography

**Other Names:**

- EC

**Type:** PROCEDURE

#### Intervention 5

**Arm Group Labels:**

- Arm A (doxorubicin and pembrolizumab

- Arm B (doxorubicin)

**Description:** Undergo MUGA scan

**Name:** Multigated Acquisition Scan

**Other Names:**

- Blood Pool Scan

- Equilibrium Radionuclide Angiography

- Gated Blood Pool Imaging

- Gated Heart Pool Scan

- MUGA

- MUGA Scan

- Multi-Gated Acquisition Scan

- Radionuclide Ventriculogram Scan

- Radionuclide Ventriculography

- RNVG

- SYMA Scanning

- Synchronized Multigated Acquisition Scanning

**Type:** PROCEDURE

#### Intervention 6

**Arm Group Labels:**

- Arm A (doxorubicin and pembrolizumab

**Description:** Given IV

**Name:** Pembrolizumab

**Other Names:**

- BCD-201

- Keytruda

- Lambrolizumab

- MK-3475

- Pembrolizumab Biosimilar BCD-201

- Pembrolizumab Biosimilar QL2107

- QL2107

- SCH 900475

**Type:** BIOLOGICAL

### Outcomes Module

#### Primary Outcomes

**Description:** Will be compared between the treatment arms (doxorubicin + pembrolizumab versus \[vs\] doxorubicin alone). The comparison of PFS between treatment arms will be done using a stratified (on Eastern Cooperative Oncology group \[ECOG\] performance status \[0 vs 1\]) log-rank test with a 5% type I error (1-sided).

**Measure:** Progression free survival (PFS)

**Time Frame:** From randomization to documented progression (per Response Evaluation Criteria in Solid Tumors [RECIST] version [v] 1.1 or death from any cause without prior progression, up to 5 years

#### Secondary Outcomes

**Description:** Will be compared between doxorubicin + pembrolizumab vs doxorubicin alone to test the strategy of upfront pembrolizumab vs second line pembrolizumab.

**Measure:** Overall survival

**Time Frame:** From randomization to death, up to 5 years

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Patient must be \>= 18 years of age
* Patient must have a confirmed histopathologic diagnosis of undifferentiated pleomorphic sarcoma (UPS) or a related poorly differentiated sarcoma. Because UPS can sometimes exist in a spectrum among related diagnoses, the following additional diagnostic will be allowed, but not limited to:

  * Pleomorphic sarcoma with inflammation or with limited areas of differentiation
  * Pleomorphic sarcoma with giant cells
  * Malignant fibrous histiocytoma (including storiform-pleomorphic and inflammatory subtypes)
  * Myxofibrosarcoma, poorly differentiated sarcoma not otherwise specified (NOS)
  * Undifferentiated spindle cell sarcoma
  * Pleomorphic dermal sarcoma
  * Poorly differentiated spindle cell sarcoma NOS Any of these subtypes may have areas of focal myogenic differentiation
* Patient must have metastatic or unresectable sarcoma
* Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:

  * Has achieved menarche at some point
  * Has not undergone a hysterectomy or bilateral oophorectomy; or
  * Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
* Patient must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study. Contraception measures must continue for 6 months after the last dose of doxorubicin for patients of child bearing potential and for 3 months after the last dose of doxorubicin for male patients with partners of child bearing potential. Contraception measures must also continue for 4 months after the last dose of pembrolizumab for patients of child bearing potential
* Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible
* Patient must have a left ventricular ejection Fraction (LVEF) \> 50% by either MUGA scan or echocardiogram obtained within 28 days prior to randomization
* Absolute neutrophil count (ANC) ≥ 1,500 cells/m\^3 (must be obtained ≤ 7 days prior to protocol randomization)
* Platelets ≥ 75,000 cells/m\^3 (must be obtained ≤ 7 days prior to protocol randomization)
* Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (must be obtained ≤ 7 days prior to protocol randomization)
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/ Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3.0 × institutional ULN (labs must be obtained ≤ 7 days prior to protocol randomization)
* Creatinine ≤ 1.5 x institutional ULN or creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (labs must be obtained ≤ 7 days prior to protocol randomization)
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
* Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
* Patient must have measurable disease. Baseline imaging, including a chest CT, of all measurable and non-measurable disease must be obtained within 28 days prior to randomization
* Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Patient must not have had prior treatment with an anthracycline
* Patient must not have a diagnosis of clinically significant immunodeficiency or an autoimmune disorder requiring the patient to use systemic steroid chronically, or systemic steroids within 7 days prior to randomization
* Patient must not have a known history of active TB (Bacillus Tuberculosis)
* Patient must not have a known hypersensitivity to doxorubicin or pembrolizumab or any of their excipients
* Patients who have received prior chemotherapy, targeted small molecule therapy or radiation therapy must have recovered from the prior therapy at the time of randomization
* Patient must have recovered adequately from any prior major surgery prior to randomization
* Patient must not have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA4 agent
* Patient must not have an autoimmune or other disease that requires the use of daily corticosteroids of \> 10 mg of prednisone (or equivalent). Patients who are on an active steroid taper at the time of randomization must finish prior to beginning study treatment. Patients who require inhaled or topical steroids are eligible

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Overall Officials

**Official 1:**

**Affiliation:** ECOG-ACRIN Cancer Research Group

**Name:** Seth M Pollack

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**Description:** 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.

**IPD Sharing:** YES

**URL:** https://grants.nih.gov/policy/sharing.htm

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000018204

- Term: Neoplasms, Connective and Soft Tissue

- ID: D000009370

- Term: Neoplasms by Histologic Type

- ID: D000009369

- Term: Neoplasms

- ID: D000051642

- Term: Histiocytoma

- ID: D000018218

- Term: Neoplasms, Fibrous Tissue

- ID: D000009372

- Term: Neoplasms, Connective Tissue

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: All

- Name: All Conditions

- Abbrev: BXM

- Name: Behaviors and Mental Disorders

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M15327

- Name: Sarcoma

- Relevance: HIGH

- As Found: Sarcoma

- ID: M26812

- Name: Histiocytoma, Malignant Fibrous

- Relevance: HIGH

- As Found: Undifferentiated Pleomorphic Sarcoma

- ID: M3724

- Name: Aggression

- Relevance: LOW

- As Found: Unknown

- ID: M26795

- Name: Histiocytoma

- Relevance: LOW

- As Found: Unknown

- ID: M20350

- Name: Neoplasms, Connective and Soft Tissue

- Relevance: LOW

- As Found: Unknown

- ID: M12315

- Name: Neoplasms by Histologic Type

- Relevance: LOW

- As Found: Unknown

- ID: M20364

- Name: Neoplasms, Fibrous Tissue

- Relevance: LOW

- As Found: Unknown

- ID: M12317

- Name: Neoplasms, Connective Tissue

- Relevance: LOW

- As Found: Unknown

- ID: T5284

- Name: Soft Tissue Sarcoma

- Relevance: HIGH

- As Found: Sarcoma

- ID: T5790

- Name: Undifferentiated Pleomorphic Sarcoma

- Relevance: HIGH

- As Found: Undifferentiated Pleomorphic Sarcoma

### Condition Browse Module - Meshes

- ID: D000012509

- Term: Sarcoma

- ID: D000051677

- Term: Histiocytoma, Malignant Fibrous

### Intervention Browse Module - Ancestors

- ID: D000074322

- Term: Antineoplastic Agents, Immunological

- ID: D000000970

- Term: Antineoplastic Agents

- ID: D000082082

- Term: Immune Checkpoint Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000000903

- Term: Antibiotics, Antineoplastic

- ID: D000059005

- Term: Topoisomerase II Inhibitors

- ID: D000059003

- Term: Topoisomerase Inhibitors

- ID: D000004791

- Term: Enzyme Inhibitors

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: Infe

- Name: Anti-Infective Agents

### Intervention Browse Module - Browse Leaves

- ID: M7492

- Name: Doxorubicin

- Relevance: HIGH

- As Found: Women

- ID: M227339

- Name: Liposomal doxorubicin

- Relevance: HIGH

- As Found: Myocardial Ischemia

- ID: M349416

- Name: Pembrolizumab

- Relevance: HIGH

- As Found: Blind

- ID: M6832

- Name: Daunorubicin

- Relevance: HIGH

- As Found: Size

- ID: M2853

- Name: Immunomodulating Agents

- Relevance: LOW

- As Found: Unknown

- ID: M1346

- Name: Antineoplastic Agents, Immunological

- Relevance: LOW

- As Found: Unknown

- ID: M2342

- Name: Immune Checkpoint Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M4222

- Name: Anti-Bacterial Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4224

- Name: Antibiotics, Antitubercular

- Relevance: LOW

- As Found: Unknown

- ID: M7951

- Name: Enzyme Inhibitors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000582435

- Term: Pembrolizumab

- ID: D000004317

- Term: Doxorubicin

- ID: C000506643

- Term: Liposomal doxorubicin

- ID: D000003630

- Term: Daunorubicin

### Misc Info Module

- Version Holder: 2024-05-31
