Clear Cell Renal Cell CarcinomaPhase 2NCT03284385
Testing AZD1775 in Advanced Solid Tumors That Have a Mutation Called SETD2
A Phase 2 study testing Adavosertib in people with Clear Cell Renal Cell Carcinoma and Locally Advanced Clear Cell Renal Cell Carcinoma, run by National Cancer Institute (NCI) at 29 sites in United States.
Trial summary
This phase II trial studies how well adavosertib works in treating patients with SETD2-deficient solid tumors that have spread to other places in the body (advanced/metastatic). Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Clear Cell Renal Cell Carcinoma, Locally Advanced Clear Cell Renal Cell Carcinoma, Locally Advanced Malignant Solid Neoplasm
- What is being tested?
- Adavosertib
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 29 sitesUnited States
- Study dates
- 29 Jan 2019to 22 Apr 2027
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Cohort A: Histologically confirmed locally advanced or metastatic solid tumor malignancy other than clear cell renal cell carcinoma with progression on at least one prior systemic therapy and presence of pathogenic loss of SETD2 detected in tumor tissue detected using a Clinical Laboratory Improvement Act (CLIA)-certified next generation sequencing panel (e.g. UCSF500, FoundationOne)
- 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
- All next generation sequencing (NGS) sequencing reports will be reviewed by the University of California at San Francisco (UCSF) Molecular Tumor Board to verify pathogenicity of SETD2 mutation. Each NGS report will be redacted for Protected Health Information (PHI) prior to submission from investigational site to UCSF MTB.
- Measurable disease by RECIST 1.1 criteria
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- Absolute neutrophil count >= 1,500/mcL
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- Platelets >= 100,000/mcL
- Hemoglobin >= 9 g/dL
- Total bilirubin within normal institutional limits (WLN) or =< 1.5 x upper limit of normal (ULN) in patients with liver metastases; or total bilirubin =< 3 x ULN with direct bilirubin WLN in patients with well documented Gilbert's syndrome
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3.0 x institutional upper limit of normal (=< 5 x ULN if known liver metastases)
- Serum creatinine =< 1.5 x ULN, OR
- Creatinine clearance >= 45 ml/min (24 hour urine creatinine clearance or calculated by Cockcroft-Gault equation)
- Any prior radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment
- Female patients who are not of child-bearing potential and fertile females of childbearing potential who agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after study treatment discontinuation, who are not breastfeeding, and who have a negative serum or urine pregnancy test within 3 days prior to the start of study treatment
- 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
- Willingness and ability to comply with study and follow-up procedures
- Has read and understands the informed consent form and has given written informed consent prior to any study procedures
Who cannot join
- Use of anti-cancer treatment drug =< 21 days or 5 half-lives (whichever is shorter) prior to the first dose of AZD1775; for drugs for which 5 half-lives is =< 21 days, a minimum of 10 days between termination of the prior treatment and administration of AZD1775 treatment is required
- Previous radiation therapy completed =< 7 days prior to the start of study drugs
- Major surgical procedures =< 28 days of beginning study treatment, or minor surgical procedures =< 7 days; no waiting period required following port-a-cath or other central venous access placement
- Grade > 1 toxicity from prior therapy (except alopecia or anorexia)
- Patient has an inability to swallow oral medications; Note: patient may not have a percutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN)
- No other anticancer-therapy (chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy [except for palliative local radiotherapy]), biological therapy or other novel agent is to be permitted while the patient is receiving study medication; patients on luteinizing hormone-releasing hormone (LHRH) analogue treatment for more than 6 months are allowed entry into the study and may continue at the discretion of the investigator
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- 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
- Any known hypersensitivity or contraindication to the components of the study drug AZD1775
- Patient has had prescription or non-prescription drugs or other products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug; co-administration of aprepitant or fosaprepitant during this study is prohibited; the use of sensitive substrates of CYP3A4, such as atorvastatin, simvastatin and lovastatin, is also prohibited in this study; transporter studies (in vitro) have shown that AZD1775 is an inhibitor of breast cancer resistance protein (BCRP); herbal preparations are not allowed throughout the study; these herbal medications include but are not limited to: St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng; patients should stop using these herbal medications 7 days prior to first dose of study treatment
- Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) >= class 2
- Unstable angina pectoris
- Congestive heart failure
- Acute myocardial infarction
- Conduction abnormality not controlled with pacemaker or medication
- Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
- AZD1775 should not be given to patients who have a history of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected; AZD1775 has not been studied in patients with ventricular arrhythmias or recent myocardial infarction
- Mean resting corrected QT (QTc) interval using the Fridericia formula (QTcF) > 450 ms (i.e., grade 1 or higher) for males and > 470 ms for females on electrocardiogram (ECG) prior to initiation of study treatment obtained from 3 electrocardiograms (ECGs) obtained 2-5 minutes apart at study entry, or history of congenital long QT syndrome
- If baseline QTc on screening ECG is > 450 ms for males or > 470 ms for females:
- Check potassium and magnesium serum levels
- Correct any identified hypokalemia and/or hypomagnesemia and repeat ECG to confirm QTcF interval
- For patients with baseline heart rate (HR) < 60 bpm or > 100 bpm, manual measurement of QT interval by cardiologist is required, with Fridericia correction applied to that manual measurement to determine the QTc for eligibility consideration
- Note: For patients with HR 60-100 bpm, manual measurement of QTc interval is NOT required
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant or breastfeeding women; pregnant women are excluded from this study because AZD1775 is WEE1 inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD1775, breastfeeding should be discontinued if the mother is treated with AZD1775
- Prior treatment with WEE1 inhibitor
Trial locations and contacts
29 sites in 1 country.
29 sites in 1 country
United States29 sites
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02114
Brigham and Women's Hospital
Boston, Massachusetts, 02115
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Northwestern University
Chicago, Illinois, 60611
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, 48201
University of Kansas Clinical Research Center
Fairway, Kansas, 66205
Weisberg Cancer Treatment Center
Farmington Hills, Michigan, 48334
UT MD Anderson Cancer Center
Houston, Texas, 77030
University of Kansas Cancer Center
Kansas City, Kansas, 66160
Vanderbilt Breast Center at One Hundred Oaks
Nashville, Tennessee, 37204
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, 37232
UC Comprehensive Cancer Center at Silver Cross
New Lenox, Illinois, 60451
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
University of Chicago Medicine-Orland Park
Orland Park, Illinois, 60462
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817
UCSF Medical Center-Mount Zion
San Francisco, California, 94115
UCSF Medical Center-Mission Bay
San Francisco, California, 94158
Washington University School of Medicine
St Louis, Missouri, 63110
Siteman Cancer Center-South County
St Louis, Missouri, 63129
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, 20007
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205
About this study
Official title: A Phase 2 Study of AZD1775 in SETD2-Deficient Advanced Solid Tumor Malignancies
This phase II trial studies how well adavosertib works in treating patients with SETD2-deficient solid tumors that have spread to other places in the body (advanced/metastatic). Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Read the detailed description
PRIMARY OBJECTIVES:
- To determine the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria of adavosertib (AZD1775) in advanced solid tumor malignancies other than clear cell renal cell carcinoma with evidence of pathogenic loss of SETD2 using next-generation sequencing panel.
II. To determine the objective response rate by RECIST 1.1 criteria of AZD1775 in clear cell renal cell carcinoma with evidence of loss of SETD2 using next-generation sequencing panel.
SECONDARY OBJECTIVES:
- To determine the clinical benefit rate and duration of response of AZD1775 in SETD2-deficient tumors other than clear cell renal cell carcinoma.
II. To determine the clinical benefit rate and duration of response of AZD1775 in SETD2-deficient clear cell renal cell carcinoma subgroup.
III. To characterize the safety profile of AZD1775. IV. To determine whether H3K36me3 expression by immunohistochemical assay is associated with clinical outcomes.
OUTLINE:
Patients receive adavosertib orally (PO) once daily (QD) on days 1-5 and 8-12. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
- Conditions
- Clear Cell Renal Cell Carcinoma, Locally Advanced Clear Cell Renal Cell Carcinoma, Locally Advanced Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm, Metastatic Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v8
- Being tested
- Adavosertib
- Medical subject headings
- Carcinoma, Renal Cell, Neoplasm Metastasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AdavosertibDrug
Also called AZD 1775, AZD-1775, AZD1775, MK 1775
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Treatment (adavosertib) | Experimental | 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. Receives: Drug: Adavosertib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective response rate
Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The median duration of response will be descriptively reported using Kaplan-Meier product limit method along with 95% confidence interval. The objective response rate between cohorts will be compared using the chi-squared test.
Measured: Up to 2 years
Secondary outcomes (5)
Clinical benefit rate
Will be defined as patients who experience either objective response or stable disease for >= 6 months from start of study treatment. The clinical benefit rate across the entire study cohort will be descriptively reported along with 95% confidence interval.
Measured: Up to 2 years
Duration of response
The median duration of response will be descriptively reported using Kaplan-Meier product limit method along with 95% confidence interval.
Measured: Up to 2 years
Incidence and severity of adverse events
Will be graded by Common Toxicity Criteria version 5.0, will be descriptively reported for the safety-evaluable population.
Measured: Up to 2 years
H3K36me3 mark
Will be assessed by immunohistochemistry.
Measured: Up to 2 years
Progression free survival
The median progression-free survival for each cohort will be determined using the Kaplan-Meier product limit method and compared between cohorts using the log-rank test.
Measured: Up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Sep 2017
- Study start29 Jan 2019
- Primary completion1 Mar 2026
- Study completion22 Apr 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Clear Cell Renal Cell CarcinomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Rahul R Aggarwal, Principal investigator, Yale University Cancer Center LAO
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03284385
- Sponsor's protocol ID
- NCI-2017-01670
- Other IDs
- NCI-2017-01670, 10170, 10170, UM1CA186689
- Status last verified
- Oct 2026
- First submitted
- 14 Sep 2017
- Last updated
- 23 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
Maldonado E, Rathmell WK, Shapiro GI, Takebe N, Rodon J, Mahalingam D, Trikalinos NA, Kalebasty AR, Parikh M, Boerner SA, Balido C, Krings G, Burns TF, Bergsland EK, Munster PN, Ashworth A, LoRusso P, Aggarwal RR. A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170). Cancer Res Commun. 2024 Jul 1;4(7):1793-1801. doi: 10.1158/2767-9764.CRC-24-0213.
PubMed 38920407