What side effects are associated with this type of intervention?

Common treatments for Renal Cell Carcinoma (RCC) involving enzyme inhibition, such as tyrosine kinase inhibitors (TKIs) like sunitinib, pazopanib, axitinib, and sorafenib, are associated with several side effects. These include hypertension, palmar-plantar erythrodysesthesia (hand-foot syndrome), diarrhea, hypothyroidism, and mucosal inflammation. Additionally, these treatments can cause elevated liver enzymes, fatigue, and gastrointestinal disturbances. It is important for patients to discuss these potential side effects with their healthcare provider to manage and mitigate them effectively.

What prior FDA approvals exist?

Several FDA-approved treatments for Renal Cell Carcinoma (RCC) include enzyme inhibitors. Sorafenib and Sunitinib are approved for advanced RCC and function as multi-kinase inhibitors targeting VEGFR and other kinases. Lenvatinib, another multi-kinase inhibitor, targets VEGFRs, RET, and FGFRs and is also approved for advanced RCC. These treatments, like Adavosertib, inhibit specific enzymes involved in tumor growth and progression.

What other types of research exist?

Promising alternatives to Adavosertib for RCC patients include Pembrolizumab plus Axitinib, which has shown improved efficacy over sunitinib in the KEYNOTE-426 trial, and Tivozanib, which has demonstrated significant activity and a favorable safety profile in Phase II and III studies. Additionally, the combination of Sapanisertib and Serabelisib with Paclitaxel has shown remarkable preliminary efficacy in patients with advanced solid tumors, including RCC.

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Wee1 Kinase Inhibitor

Adavosertib for Cancer

Phase 2

Waitlist Available

Led By Rahul R Aggarwal

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

Male patients willing to abstain or use barrier contraception (i.e. condoms) for the duration of the study and for 3 months after treatment stops

Cohort B: Patients with histologically confirmed locally advanced or metastatic clear cell renal cell carcinoma (with clear cell component on pathology), who have been treated with at least one prior systemic therapy for locally advanced or metastatic disease, including either tyrosine kinase inhibitor and/or immune checkpoint inhibitor, with evidence of SETD2 mutation on CLIA-certified next generation sequencing panel

Must not have

Any known hypersensitivity or contraindication to the components of the study drug AZD1775

Known malignant central nervous system (CNS) disease other than neurologically stable, treated brain metastases - defined as metastasis having no evidence of progression or hemorrhage for at least 2 weeks after treatment; must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrollment; patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 2 years

Awards & highlights

No Placebo-Only Group

Summary

This trial studies how well adavosertib works in patients with advanced or metastatic solid tumors that lack the SETD2 gene. Adavosertib may help stop tumor growth by blocking enzymes needed for cancer cells to grow. Adavosertib is a first-in-class, small-molecule reversible inhibitor of WEE1 kinase, previously shown to have clinical activity in various cancers.

Who is the study for?

This trial is for adults with advanced solid tumors that have spread and have a SETD2 mutation. They must have tried at least one therapy, be able to swallow pills, not be pregnant or breastfeeding, use contraception if fertile, and meet certain health criteria like specific blood cell counts.

What is being tested?

The trial is testing Adavosertib's effectiveness on patients with SETD2-deficient advanced solid tumors. It's a phase II study where the drug aims to block enzymes needed for tumor growth.

What are the potential side effects?

Potential side effects of Adavosertib may include fatigue, nausea, low blood cell counts leading to increased infection risk or bleeding problems, and other common chemotherapy-related reactions.

Eligibility Criteria

Inclusion Criteria

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

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I am a male willing to use condoms during the study and for 3 months after it ends.

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I have advanced kidney cancer with a specific genetic change and have had previous treatment.

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My bilirubin levels are within the normal range, even with liver issues or Gilbert's syndrome.

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My cancer has spread, is not kidney cancer, and has a specific genetic change.

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My kidney function, measured by creatinine levels or clearance, is within the required range.

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I am mostly active and can care for myself.

Exclusion Criteria

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

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I am not allergic to the study drug AZD1775.

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I do not have active brain cancer or symptoms from previous brain metastases.

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I do not have any severe illnesses or social situations that would prevent me from following the study's requirements.

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I have been treated with a WEE1 inhibitor before.

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I am not taking any medication or herbal supplements that affect CYP3A4 enzymes.

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I have not had serious heart problems in the last 6 months.

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I have experienced side effects worse than mild from previous treatments, excluding hair loss or loss of appetite.

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I am not pregnant or breastfeeding.

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I haven't taken any cancer drugs in the last 3 weeks or within their half-life period before starting AZD1775.

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

Objective response rate

Secondary study objectives

Clinical benefit rate

Duration of response

H3K36me3 mark

+2 more

Side effects data

From 2023 Phase 1 & 2 trial • 76 Patients • NCT02095132

80%

Lymphocyte count decreased

80%

Fatigue

80%

Hypoalbuminemia

80%

White blood cell decreased

80%

Vomiting

70%

Anemia

70%

Diarrhea

70%

Abdominal pain

70%

Nausea

60%

Anorexia

50%

Sinus tachycardia

50%

Cough

50%

Fever

50%

Pleural effusion

40%

Anxiety

40%

Neutrophil count decreased

40%

Aspartate aminotransferase increased

40%

Dyspnea

40%

Headache

40%

Platelet count decreased

30%

Alopecia

30%

Hypermagnesemia

30%

Hypomagnesemia

30%

Insomnia

30%

Constipation

30%

Pain

30%

Pain in extremity

30%

Dizziness

30%

Hypertension

30%

Dehydration

30%

Hypocalcemia

30%

Weight loss

20%

Hematuria

20%

Allergic rhinitis

20%

Alanine aminotransferase increased

20%

Hyponatremia

20%

Wound infection

20%

Atelectasis

20%

Gait disturbance

20%

Hyperkalemia

20%

Hypophosphatemia

20%

Hypokalemia

20%

Myalgia

20%

Nasal congestion

20%

Osteoporosis

20%

Productive cough

20%

Dry mouth

20%

Hypotension

20%

Peripheral sensory neuropathy

10%

Alkalosis

10%

Bruising

10%

Tumor pain

10%

Muscle weakness upper limb

10%

Lymphedema

10%

Eye disorders - Other, Visual disturbance

10%

Pulmonary edema

10%

Investigations - Other, ELEVATED LDH

10%

Infections and infestations - Other, Retropharyngeal infection

10%

Skin and subcutaneous tissue disorders - Other, SMEGMA

10%

Musculoskeletal and connective tissue disorder - Other, GROWTH PLATE ABNORMALITY

10%

Skin and subcutaneous tissue disorders - Other, HAIR DEPIGMENTATION

10%

Lethargy

10%

Localized edema

10%

Photophobia

10%

Sinus bradycardia

10%

Generalized muscle weakness

10%

Muscle weakness lower limb

10%

Urine output decreased

10%

Chest wall pain

10%

Malaise

10%

Skin ulceration

10%

Hypothyroidism

10%

Acute kidney injury

10%

Hyperglycemia

10%

Hypoxia

10%

Non-cardiac chest pain

10%

Back pain

10%

Blood bilirubin increased

10%

Blurred vision

10%

Chills

10%

Dyspepsia

10%

Dysphagia

10%

Fecal incontinence

10%

Gastritis

10%

Hyperhidrosis

10%

Hypernatremia

10%

Hypertriglyceridemia

10%

Infections and infestations - Other, C. DIFF INFECTION

10%

Infections and infestations - Other, E COLI

10%

Infections and infestations - Other, E. COLI

10%

Investigations - Other, BUN increased

10%

Investigations - Other, elevated LDH

10%

Lipase increased

10%

Metabolism and nutrition disorders - Other, CACHEXIA

10%

Mucositis oral

10%

Oculomotor nerve disorder

10%

Paresthesia

10%

Proteinuria

10%

Respiratory, thoracic and mediastinal disorders - Other,

10%

Respiratory, thoracic and mediastinal disorders - Other, TACHYPNEA

10%

Scoliosis

10%

Skin hypopigmentation

10%

Surgical and medical procedures - Other, G-tube placement

10%

Tinnitus

10%

Urinary retention

10%

Skin and subcutaneous tissue disorders - Other, TUMOR BLEEDING

10%

Urinary tract obstruction

10%

Alkaline phosphatase increased

10%

Bone pain

10%

Creatinine increased

10%

Dysgeusia

10%

Electrocardiogram QT corrected interval prolonged

10%

Investigations - Other, VIT D DEFICIENCY

10%

Hearing impaired

10%

Investigations - Other, bicarbonate serum low

10%

Neck pain

10%

Sore throat

100%

80%

60%

40%

20%

Study treatment Arm

Part D, Rhabdomyosarcoma

Part A, Dose Level 1

Part A, Dose Level 2

Part A, Dose Level 3

Part A, Dose Level 4

Part A, Dose Level 5

Part A, PK Expansion

Part B, Neuroblastoma

Part C, Medulloblastoma/CNS PNET

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 (adavosertib)Experimental Treatment1 Intervention

Patients receive adavosertib PO QD on days 1-5 and 8-12. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Adavosertib

2015

Completed Phase 2

~570

0 / 15Eligibility 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

Common treatments for Renal Cell Carcinoma (RCC) include targeted therapies, immunotherapies, and enzyme inhibitors. Targeted therapies, such as VEGFR inhibitors, work by blocking the blood supply to the tumor, effectively starving it of nutrients needed for growth. Immunotherapies, like checkpoint inhibitors, enhance the body's immune response against cancer cells. Enzyme inhibitors, such as adavosertib, target specific enzymes necessary for cancer cell proliferation, thereby halting tumor growth. These mechanisms are crucial for RCC patients as they offer personalized treatment options that can be more effective and have fewer side effects compared to traditional chemotherapy.

Pharmacokinetics and Safety of Olaparib in Patients with Advanced Solid Tumours and Renal Impairment.Sunitinib: Ten Years of Successful Clinical Use and Study in Advanced Renal Cell Carcinoma.Renal carcinoma pharmacogenomics and predictors of response: Steps toward treatment individualization.