Neoplasms

All Conditions

Rare Diseases

Sarcoma

Leiomyosarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Soft Tissue Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Peposertib

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Protein Kinase Inhibitors

Patients receive peposertib PO BID and pegylated liposomal doxorubicin hydrochloride IV QD during treatment cycles on study. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo CT or MRI throughout the trial. Patients also undergo blood sample collection and tissue biopsy during screening and on the trial.

Biopsy

Undergo blood and tissue sample collection

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Pegylated Liposomal Doxorubicin Hydrochloride

Site Public Contact

A P. Chen

Candace L. Haddox

Scott M. Schuetze

Melissa A. Burgess

Elise F. Nassif

Candace L Haddox

This phase I trial tests the safety, side effects, and best dose of combination therapy with liposomal doxorubicin and peposertib in treating patients with sarcoma that has spread from where it first started, to other places in the body (metastatic), or cannot be removed by surgery (unresectable) and for which no known cure is available (advanced). Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's DNA and may kill cancer cells. It also blocks a certain enzyme needed for cell division and DNA repair. Liposomal doxorubicin is a form of the anticancer drug doxorubicin that is contained inside very tiny, fat-like particles. Liposomal doxorubicin may have fewer side effects and work better than other forms of the drug. Peposertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It may also enhance the activity of chemo- and radiotherapy. There is some pre-clinical evidence in animal models that combining peposertib with liposomal doxorubicin can shrink or stabilize certain types of cancer for longer than either drug alone, but it is not known if this will happen in people. Combination therapy with liposomal doxorubicin and peposertib may be effective in patients with advanced sarcoma.

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of peposertib in combination with low-dose pegylated liposomal doxorubicin hydrochloride (liposomal doxorubicin) as evaluated by the dose-limiting toxicity (DLT) rate at each tested dose level. (Dose Escalation) II. To determine the recommended phase 2 dose (RP2D) of liposomal doxorubicin and peposertib combination and determine the maximal tolerated dose (MTD) if identified. (Dose Escalation) III. To obtain a more precise determination of adverse events (e.g. dose limiting toxicities estimate at the selected dose). (Dose Expansion)

SECONDARY OBJECTIVES:

I. To assess the pharmacokinetics of peposertib and liposomal doxorubicin used in combination with each other. (Dose Escalation) II. To estimate the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with leiomyosarcoma treated with peposertib and low-dose liposomal doxorubicin. (Dose Expansion) III. To estimate the progression free survival (PFS) in patients with leiomyosarcoma treated with peposertib and low-dose liposomal doxorubicin. (Dose Expansion) IV. To assess the pharmacokinetics of peposertib and liposomal doxorubicin used in combination with each other. (Dose Expansion) V. To assess whether DNA damage is exaggerated by the low-dose liposomal doxorubicin in combination with peposertib in patients with homologous recombination (HR)-deficiency. (Dose Expansion)

CORRELATIVE OBJECTIVES:

I. To test the hypothesis that soft tissue sarcomas (STS) with homologous recombination deficiency (HRD) like leiomyosarcomas (LMS) will be more susceptible to deoxyribonucleic acid (DNA)-PKi in combination with low-dose liposomal doxorubicin.

II. To test the hypothesis that gammaH2AX and pNBS1 can be used as pharmacodynamic biomarkers of response to DNA-PKi in combination with low-dose liposomal doxorubicin.

III. To test the hypothesis that disease activity correlates with circulating tumor DNA levels in the plasma.

OUTLINE: This is a dose-escalation study of peposertib and liposomal doxorubicin followed by a dose-expansion study.

Patients receive peposertib orally (PO) twice daily (BID) and pegylated liposomal doxorubicin hydrochloride intravenously (IV) once daily (QD) during treatment cycles on study. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial. Patients also undergo blood sample collection and tissue biopsy during screening and on the trial.

Patients are followed for 30 days after removal from study or until death, whichever occurs first.

Testing Low-Dose Common Chemotherapy (Liposomal Doxorubicin) in Combination With an Anti-Cancer Drug, Peposertib, in Advanced Sarcoma

A Phase 1 Study of Peposertib (M3814) and Low-Dose Liposomal Doxorubicin ( (Doxil®) in Patients With Metastatic Leiomyosarcoma and Other Soft Tissue Sarcomas

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.

The number and type of DLT seen at each dose level will be provided. The adverse events (AEs) will also be summarized by AE type and the maximum grade of the AE experienced by the patient for each dose level. DLT will be used to determine the recommended phase 2 dose (RP2D) of study drugs.

AEs will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Assessed with Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.

The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. Patients who are alive at the time of analysis without a documented disease progression will be censored at the time of their last tumor evaluation.

Will be defined by HRD score and mutational signature analysis.

Will be defined by gammaH2AX and NBS1 S343 phosphorylation based on the National Clinical Laboratory Network DDR3 assay.

National Cancer Institute (NCI)

Anticonvulsants

Central Nervous System Depressants

Psychotropic Drugs

Gemcitabine

Bevacizumab

Docetaxel

Valproic Acid

Histone Deacetylase Inhibitors

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Antimetabolites

Tubulin Modulators

Antimitotic Agents

Neurotransmitter Agents

Bevacizumab Combined with Gemcitabine, Docetaxel and Valproic Acid in Advanced Sarcoma

Bevacizumab, Gemcitabine, Docetaxel and Valproic Acid

Mohammed Milhem, MD

The purpose of this study is to test the combination of the chemotherapy drugs Gemcitabine, bevacizumab, and docetaxel with valproic acid to treat patients with metastatic sarcoma. Valproic acid is used by people who have seizures to prevent seizures from happening; however, its use in cancer is investigational. This study will help define the proper dosing of this valproic acid. We will assess the safety of valproic acid with the combination of the above chemotherapy drugs and check for possible side effects. Valproic acid may improve the function of the chemotherapy drugs against the cancer.

Soft tissue sarcomas (STS) are a heterogeneous group of benign and malignant tumors of various supportive tissues arising from the mesoderm. There are 56 known subtypes classified by the tissue of origin. Soft tissue sarcomas account for 1% of all human malignancies. These tumors share a common mesenchymal origin with the vasculature. Many of the signaling pathways involved in angiogenesis also drive sarcoma tumor cell growth. Autocrine and paracrine vascular endothelial growth factor (VEGF) - and platelet-derived growth factor (PDGF)-mediated growth plays a role in the pathogenesis of several sarcoma subtypes1. Despite promising preclinical data supporting a role for angiogenesis inhibition in sarcoma, relatively few clinical trials have evaluated antiangiogenic therapy in sarcoma.

Most of the studies for the use of anti-angiogenic drugs have been taken from phase I trials of refractory solid tumors showing a lack of response in sarcomas. This may be due to an inadequate dose, wrong sequence of the treatment or lack of studies with combination treatments. Given the heterogeneity of sarcomas there may be a benefit in certain subgroups that can easily be missed. A recent clinical trial has shown improved cytotoxic cell kill and response rates by epigenetically modifying the tumor environment prior to chemotherapy. It is believed that the efficacy of angiogenesis inhibitors has been shown to be greatly improved when they are combined with other anticancer drugs.

Tumor metastasis is highly dependent on angiogenesis progressing through a metastatic cascade that includes primary tumor growth, modification of tumor cell growth and behavior and formation of new blood vessels. This angiogenic switch is believed to be the result of changes in the balance of angiogenesis stimulators, inhibitors and modulators present at the site of the tumor growth. These changes are due to both genetic alterations involving RAS, RAF, MYC, SRC, EGFR and HER-2 and tumor suppressor genes and epigenetic circumstances such as hypoxia, inflammation or hormonal stimulation. It is clear that vascular endothelial growth factor (VEGF) has emerged as the key stimulatory molecule for promoting angiogenesis in a variety of human malignancies. Other pro-angiogenic factors can be induced or amplified in the presence of hypoxia hypoglycemia, inflammatory cytokines and altered cell-cell contact. Thus it would be of interest to combine epigenetic modifiers like Valproic acid, a histone deacetylase inhibitor, with Bevacizumab, an anti-angiogenic agent against VEGF and standard chemotherapy (Gemcitabine /docetaxel) to better modulate the cytotoxic effects against sarcomas.

Bevacizumab, Chemotherapy and Valproic Acid in Advanced Sarcomas

A Pilot Study Targeting Angiogenesis Using Bevacizumab Combined With Chemotherapy and Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas

Dose-limiting toxicities per CTCAE 4.0; grade 4 hematologic toxicity; grade 3 or 4 hepatotoxicity.

Genentech, Inc.

Mohammed M Milhem

Clinical Associate Professor

Anthracycline-naïve patients will receive combination of PM01183 and Doxorubicin per cycle.

* PM01183 predetermined dose daily via IV per cycle
* Doxorubicin predetermined dose daily via IV per cycle

Prior anthracycline exposure and without prior gemcitabine exposure

* PM01183 predetermined dose given twice via IV per cycle
* Gemcitabine predetermined dose given twice via IV per cycle

Patients who have received at least both prior anthracycline and prior gemcitabine

-PM01183 predetermined dose once via IV per cycle

PM01183

Gregory Cote, MD PhD

This research study is investigating a drug called PM01183 alone and in combination with chemotherapy drugs called gemcitabine or doxorubicin as a possible treatment for metastatic or unresectable Sarcoma.

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

PM01183 is a new drug that is believed to bind DNA cause double strands of DNA to break. This drug has been studied in previous research studies, and these suggest that it may slow or stop the growth of cancers. The FDA (the U.S. Food and Drug Administration) has not approved PM01183 as a treatment for any disease.

In this research study, the investigators are trying to assess the effects, good or bad, that PM01183, administered either alone or in combination with gemcitabine or doxorubicin has on metastatic or unresectable sarcoma.

A Phase II Multi-Strata Study of PM01183 as a Single Agent or in Combination With Conventional Chemotherapy in Metastatic and/or Unresectable Sarcomas

The number of participants that achieved either Stable Disease (SD) or a Partial Response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) at 24 weeks.

* Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
* Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

The overall response rate is the number of participants that achieved either Stable Disease (SD), a Partial Response (PR), or a Complete Response (CR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The overall response rate is the best response recorded from the start of treatment until disease progression/recurrence.

* Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.
* Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
* Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Summary of the serious adverse events (SAE) experienced by participants that were deemed to be at least possibly related to PM01183 when administered alone or with Doxorubicin or Gemcitabine. Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE v4).

Dana-Farber Cancer Institute

PharmaMar

Massachusetts General Hospital

MD PhD

Anthracycline-naïve patients will receive combination of PM01183 and Doxorubicin per cycle.

* PM01183 predetermined dose daily via IV per cycle
* Doxorubicin predetermined dose daily via IV per cycle

PM01183

Doxorubicin

Stratum A

Prior anthracycline exposure and without prior gemcitabine exposure

* PM01183 predetermined dose given twice via IV per cycle
* Gemcitabine predetermined dose given twice via IV per cycle

PM01183

Gemcitabine

Stratum B

Patients who have received at least both prior anthracycline and prior gemcitabine

-PM01183 predetermined dose once via IV per cycle

PM01183

Stratum C

PM01183 and Doxorubicin

PM01183 and Gemcitabine

Single Agent PM01183

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

White

Black or African-American

Asian

More Than One Race

Other

Race/Ethnicity, Customized

United States

Region of Enrollment

Gregory Cote, M.D., Ph.D

Two participants (one from the PM01183 and Doxorubicin arm and one from the PM01183 alone arm) were not able to be evaluated for response.

Disease Control Rate

Complete Response

Partial Response

Stable Disease

Unknown

Overall Response Rate

Diarrhea

Febrile neutropenia

Lymphocyte count decreased

Nausea

Neutrophil count decreased

Platelet count decreased

Port Infection

Vomiting

White blood cell decreased

Any Treatment Related SAE

Treatment Related Serious Adverse Events

Overall Study

Ifosfamide

Isophosphamide mustard

Ridaforolimus combined with doxorubicin/ifosfamide/mesma (AIM)

Ridaforolimus combined with docetaxel and gemcitabine (TG)

Ridaforolimus administered orally 5 days per week in combination with standard chemotherapy

ridaforolimus

Monica Mita, MD

Ridaforolimus has been tested in almost 2 dozen studies; however, it has not previously been tested in combination with the standard of care chemotherapy for sarcoma as this study will. We will be looking to see if Ridaforolimus given with SOC chemo (AIM or TG) is well tolerated and to determine a Phase 2 dose.

Study of Oral Ridaforolimus in Combination With Standard Chemotherapy for Soft Tissue Sarcoma

Phase Ib Study of Oral Ridaforolimus in Combination With Standard Chemotherapy for Patients With Advanced Unresectable Soft Tissue Sarcoma

Defining the maximum tolerated dose (MTD) and recommended Phase II dose for the combination ridaforolimus and SOC chemotherapy

Any evidence of antitumor activity--as measured by response rate (RECIST).

Ridaforolimus pharmacokinetics when given in combination with SOC chemotherapy. Limited PK for SOC chemotherapy when combined with ridaforlimus. We will measure change in concentration of Ridaforolimus when combined with chemotherapy.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Testing Low-Dose Common Chemotherapy (Liposomal Doxorubicin) in Combination With an Anti-Cancer Drug, Peposertib, in Advanced Sarcoma	NCT05711615	Metastatic Leio... Metastatic Sarc... Metastatic Soft... Unresectable Le... Unresectable Sa... Unresectable So...	Biopsy Biospecimen Col... Computed Tomogr... Magnetic Resona... Pegylated Lipos... Peposertib	18 Years -	National Cancer Institute (NCI)
Bevacizumab, Chemotherapy and Valproic Acid in Advanced Sarcomas	NCT01106872	Sarcoma Soft Tissue Sar... Locally Advance... Unresectable Sa... Metastatic Sarc...	Bevacizumab, Ge...	18 Years - 99 Years	University of Iowa
A Phase II Multi-Strata Study of PM01183 as a Single Agent or in Combination With Conventional Chemotherapy in Metastatic and/or Unresectable Sarcomas	NCT02448537	Metastatic Sarc...	PM01183 Doxorubicin Gemcitabine	18 Years - 75 Years	Massachusetts General Hospital
Bevacizumab, Chemotherapy and Valproic Acid in Advanced Sarcomas	NCT01106872	Sarcoma Soft Tissue Sar... Locally Advance... Unresectable Sa... Metastatic Sarc...	Bevacizumab, Ge...	18 Years - 99 Years	University of Iowa
Study of Oral Ridaforolimus in Combination With Standard Chemotherapy for Soft Tissue Sarcoma	NCT01296659	Soft Tissue Sar...	ridaforolimus	18 Years -	The University of Texas Health Science Center at San Antonio

Spots Global Cancer Trial Database for unresectable sarcoma