What is the mechanism of action of this treatment?

The most common treatments for Uterine Leiomyosarcoma (LMS) include PARP inhibitors like Olaparib and chemotherapy agents like Temozolomide. Olaparib works by inhibiting the PARP enzyme, which is crucial for repairing DNA mutations in cancer cells, thereby leading to cell death. Temozolomide, on the other hand, damages the DNA of cancer cells, preventing them from dividing and spreading. This combination is significant for LMS patients as it targets the cancer cells through different mechanisms, potentially improving treatment efficacy and patient outcomes.

What side effects are associated with this type of intervention?

Olaparib, a PARP inhibitor, commonly causes side effects such as nausea, fatigue, vomiting, and anemia. Serious (grade 3/4) toxicities are less frequent but can include severe anemia and other hematologic issues. Temozolomide, a chemotherapy drug, often leads to side effects like nausea, vomiting, fatigue, and myelosuppression, which includes conditions like anemia, neutropenia, and thrombocytopenia. Both drugs can cause gastrointestinal disturbances and general weakness, which are typical of many cancer treatments.

What prior FDA approvals exist?

There is no specific mention of prior FDA approvals for the combination of Olaparib and Temozolomide for the treatment of Uterine Leiomyosarcoma in the provided context. However, Olaparib, a PARP inhibitor, has been studied in various cancers, including ovarian cancer, where it has shown efficacy. Temozolomide is a chemotherapy drug that has been used in different cancer treatments, including glioblastoma. For Uterine Leiomyosarcoma, treatments often involve chemotherapy agents like doxorubicin and gemcitabine-based combinations, but specific FDA approvals for the combination of Olaparib and Temozolomide in LMS are not detailed in the provided information.

What other types of research exist?

Promising novel alternatives for Uterine Leiomyosarcoma patients include: 1) Trabectedin, which has shown efficacy in phase III trials for metastatic leiomyosarcoma after failure of conventional chemotherapy. 2) Aromatase inhibitors like Letrozole and Anastrozole, particularly for patients with estrogen and/or progesterone receptor-positive tumors. 3) mTOR inhibitors such as Temsirolimus, which have been effective in certain sarcomas. 4) Multitargeted tyrosine kinase inhibitors like Sunitinib and Regorafenib, which have shown promise in phase II trials for various soft tissue sarcomas.

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PARP Inhibitor

Olaparib + Temozolomide for Leiomyosarcoma

Phase 2

Waitlist Available

Led By Matthew Ingham

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patients must be >= 18 years of age. Uterine LMS affects older adults and is rarely encountered in children and adolescents.

Patients must have histologically documented LMS of uterine origin. Pathology review and confirmation of diagnosis will occur at the site enrolling the patient on this study.

Must not have

History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib or TMZ

Concomitant use of known strong or moderate CYP3A inhibitors

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 2 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing olaparib and temozolomide in patients with advanced uterine leiomyosarcoma. Olaparib stops cancer cells from repairing themselves, while temozolomide kills or stops the growth of cancer cells. The combination may be more effective than using either drug alone.

Who is the study for?

Adults with advanced uterine leiomyosarcoma that's spread or can't be surgically removed, who've had prior treatment failure or intolerance. Must be able to swallow pills, have adequate organ function, use effective contraception if needed, and agree to study procedures.

What is being tested?

The trial tests a combination of Olaparib (a PARP inhibitor preventing tumor DNA repair) and Temozolomide (chemotherapy), aiming to see if they're more effective together against this cancer than when used separately.

What are the potential side effects?

Potential side effects include nausea, fatigue, blood cell count changes leading to increased infection risk or bleeding problems, liver function alterations, and allergic reactions related to the drugs' components.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 years old or older.

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My cancer is a type of uterine sarcoma confirmed by tissue analysis.

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My advanced LMS has worsened or not tolerated previous treatment.

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I am 18 years old or older.

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My cancer cannot be removed by surgery and has spread.

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I am not pregnant.

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My cancer is a type of uterine cancer confirmed by tissue analysis.

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I am postmenopausal or cannot have children.

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My kidney function is normal or only mildly reduced.

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I am using two reliable birth control methods if I can have children and am sexually active.

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My cancer cannot be removed by surgery and has spread.

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I can receive temozolomide as a standard treatment.

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I can take care of myself but might not be able to do heavy physical work.

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I can take care of myself but might not be able to do active work.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am allergic to medications similar to olaparib or TMZ.

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I am not taking strong or moderate drugs that affect liver enzyme CYP3A.

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I am not taking any strong or moderate drugs that affect liver enzymes.

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I do not have any unmanaged ongoing illnesses.

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I do not have stomach or bowel problems affecting medicine absorption.

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I have not had major surgery in the last 2 weeks.

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My diagnosis is MDS, AML, or my tests show I might have these.

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I have not been treated with PARP inhibitors or drugs like dacarbazine/temozolomide.

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I currently have cancer that has spread to my brain or spinal cord.

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I have side effects from previous cancer treatments that are not severe.

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I had another cancer but have been free of it for 5 years or more.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 2 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Confirmed Objective Response Rate (ORR) (Complete Response + Partial Response)

Secondary study objectives

Number of Patients Experiencing Adverse Events

Progression-free Survival (PFS)

Proportion of MGMT Protein Expression in Uterine LMS Tumors

+2 more

Side effects data

From 2016 Phase 2 trial • 175 Patients • NCT01055314

36%

Febrile neutropenia

31%

Death NOS

30%

Diarrhea

22%

Pain

21%

Hyperglycemia

16%

Anorexia

16%

Infections and infestations - Other, specify

16%

Alanine aminotransferase increased

14%

Hypokalemia

13%

Nausea

11%

Hyponatremia

10%

Weight loss

Aspartate aminotransferase increased

Mucositis oral

Anemia

Vomiting

Constipation

Dehydration

Hypophosphatemia

Platelet count decreased

Sepsis

Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify

Catheter related infection

Colitis

Abdominal pain

Hypotension

White blood cell decreased

GGT increased

Hypocalcemia

Urinary retention

Hypoalbuminemia

Fever

Typhlitis

Anxiety

Neutrophil count decreased

Urinary tract infection

Peripheral motor neuropathy

Enterocolitis

Lipase increased

Pleural effusion

Serum amylase increased

Skin infection

Epistaxis

Urinary tract obstruction

Blood bilirubin increased

Lymphocyte count decreased

Syncope

Wound infection

Dermatitis radiation

Hypertension

Sinus tachycardia

Edema limbs

Bone pain

Dyspnea

Hematuria

Hypercalcemia

Vulval infection

Upper gastrointestinal hemorrhage

Thromboembolic event

Depressed level of consciousness

Stridor

Allergic reaction

Back pain

Lung infection

Urticaria

Acute kidney injury

Muscle weakness lower limb

Musculoskeletal and connective tissue disorder - Other, specify

Pain in extremity

Peripheral sensory neuropathy

Proctitis

Skin ulceration

Apnea

Stoma site infection

Tumor pain

Left ventricular systolic dysfunction

Pancreatitis

Portal hypertension

Rectal hemorrhage

Creatinine increased

Enterocolitis infectious

Hyperkalemia

Investigations - Other, specify

Abdominal distension

Heart failure

Ascites

Vascular disorders - Other, specify

Anal hemorrhage

Penile pain

Vasovagal reaction

Gastrointestinal disorders - Other, specify

Soft tissue infection

Delirium

Tracheitis

Hepatobiliary disorders - Other, specify

Seizure

Esophageal pain

Anal mucositis

Menorrhagia

Sore throat

Bone marrow hypocellular

Anaphylaxis

Fracture

Hydrocephalus

Device related infection

Tooth infection

Gastric ulcer

Sinusitis

Skin and subcutaneous tissue disorders - Other, specify

Pharyngitis

Pyramidal tract syndrome

Anal ulcer

Depression

Ejection fraction decreased

Rash maculo-papular

Pruritus

Myositis

Nail infection

Pain of skin

Pleuritic pain

Pneumonitis

Pneumothorax

Postoperative hemorrhage

Renal and urinary disorders - Other, specify

Respiratory, thoracic and mediastinal disorders - Other, specify

Salivary duct inflammation

Small intestine infection

Alkaline phosphatase increased

Appendicitis

Spinal fracture

Disseminated intravascular coagulation

Ear and labyrinth disorders - Other, specify

Endocrine disorders - Other, specify

Esophageal stenosis

Esophagitis

Gastric hemorrhage

Gum infection

Tumor lysis syndrome

Upper respiratory infection

Hypertriglyceridemia

Hypoxia

Ileus

INR increased

Laryngeal edema

Multi-organ failure

Myelodysplastic syndrome

Oral hemorrhage

Oral pain

Pulmonary edema

Rectal fistula

Rectal pain

Respiratory failure

Bladder spasm

Chest wall pain

Confusion

Congenital, familial and genetic disorders - Other, specify

CPK increased

Dizziness

Encephalopathy

Eye disorders - Other, specify

Generalized muscle weakness

Hoarseness

Hypernatremia

Hypoglycemia

Hypomagnesemia

Insomnia

Irregular menstruation

Irritability

Joint range of motion decreased cervical spine

Kyphosis

Lethargy

Headache

Laryngeal mucositis

Pelvic pain

Esophageal infection

Abdominal infection

Acidosis

Anal fistula

Fall

Fatigue

Gait disturbance

100%

80%

60%

40%

20%

Study treatment Arm

Group 1 (Chemotherapy, Radiation Therapy, Cixutumumab)

Group 2 (Chemotherapy, Radiation Therapy, Temozolomide)

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (olaparib, temozolomide)Experimental Treatment5 Interventions

Patients receive olaparib PO BID and temozolomide PO QD on days 1-7 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI throughout the trial and undergo tumor biopsy at screening and on study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Computed Tomography

2017

Completed Phase 2

~2790

Core Biopsy

2013

N/A

~130

Magnetic Resonance Imaging

2017

Completed Phase 3

~1180

Olaparib

2007

Completed Phase 4

~2190

Temozolomide

2010

Completed Phase 3

~1880

0 / 25Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Uterine Leiomyosarcoma (LMS) include PARP inhibitors like Olaparib and chemotherapy agents like Temozolomide. Olaparib works by inhibiting the PARP enzyme, which is crucial for repairing DNA mutations in cancer cells, thereby leading to cell death. Temozolomide, on the other hand, damages the DNA of cancer cells, preventing them from dividing and spreading. This combination is significant for LMS patients as it targets the cancer cells through different mechanisms, potentially improving treatment efficacy and patient outcomes.

Integrating Precision Medicine into the Contemporary Management of Gynecologic Cancers.Treatment of Pediatric Glioblastoma with Combination Olaparib and Temozolomide Demonstrates 2-Year Durable Response.PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer.