Olaparib for Kidney Cancer

(ORCHID Trial)

Overseen By Rana Sullivan, RN, BSN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Uncontrolled brain metastases, MDS/AML, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 6 months

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests olaparib, a medication, to evaluate its effectiveness for individuals with kidney cancer that has metastasized. Researchers aim to determine if olaparib benefits those with specific genetic mutations who have previously tried treatments like immune therapy or anti-VEGF therapy. Suitable participants have metastatic kidney cancer, possess one of these genetic mutations, and have undergone at least one immune checkpoint inhibitor or anti-VEGF therapy. The trial seeks to assess whether olaparib can slow or halt cancer growth in these patients. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for strong or moderate CYP3A inhibitors and inducers before starting olaparib. You may need to stop these medications 2 to 5 weeks prior, depending on the specific drug. If you are on these medications, discuss with your doctor about possible alternatives or adjustments.

Is there any evidence suggesting that olaparib is likely to be safe for humans?

Research has shown that olaparib is generally well-tolerated by many cancer patients. In past studies with breast cancer patients, some experienced side effects, but these were often manageable. Common side effects included nausea, tiredness, and blood issues, such as anemia (a low red blood cell count).

Serious side effects were less common, with fewer than 10% of patients experiencing them, mostly related to blood counts. The FDA has already approved olaparib for other cancers, which adds confidence in its safety.

In this trial for kidney cancer, the starting dose of olaparib is lower for the first month. This approach allows researchers to monitor for any serious side effects and adjust treatment if needed. Regular check-ups are part of the trial to ensure safety.

Overall, while no treatment is without risks, olaparib has a history of being safe for many patients, with side effects that are often predictable and manageable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for kidney cancer?

Olaparib is unique because it specifically targets genetic mutations linked to DNA repair, such as those in BRCA1 and BRCA2, which are not typically addressed by standard kidney cancer treatments. Most current treatments for kidney cancer involve immune checkpoint inhibitors or anti-VEGF therapies, which focus on enhancing the immune response or inhibiting blood vessel growth in tumors. Olaparib works by inhibiting the PARP enzyme, leading to cancer cell death in tumors with DNA repair deficiencies. Researchers are excited about this treatment because it offers a targeted approach that could potentially be more effective for patients with specific genetic profiles, offering new hope for those who haven't responded well to existing therapies.

What evidence suggests that olaparib might be an effective treatment for kidney cancer?

Studies have shown that olaparib, a PARP inhibitor, holds promise for patients with advanced kidney cancer who have certain genetic changes. In this trial, participants with metastatic renal cell carcinoma and specific genetic mutations will receive olaparib. Early research suggests that olaparib effectively targets tumors with these specific changes. These changes affect how cancer cells repair their DNA, and olaparib blocks a protein that helps fix damaged DNA, slowing cancer growth. Initial studies demonstrated that olaparib is active in these cancers, offering hope to patients who have already tried other treatments like immune therapies or anti-VEGF therapy. While more research is needed, these early results encourage those with kidney cancer with these genetic traits. ^{2 5 6 7 8}

Who Is on the Research Team?

Mark C Markowski, MD, Ph.D

Principal Investigator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Are You a Good Fit for This Trial?

Adults with metastatic renal cell carcinoma and specific gene mutations who've had prior anti-cancer treatments can join. They must have a certain level of blood counts, organ function, and life expectancy. Women should not be pregnant or breastfeeding, and men must use contraception.

Inclusion Criteria

Your platelet count is at least 100 billion per liter.

Your white blood cell count is at least 1.5 times 10 raised to the power of 9 per liter.

Your liver enzymes (AST/SGOT and ALT/SGPT) should not be too high, unless you have cancer in your liver, in which case they can be a little higher.

Exclusion Criteria

I cannot take pills by mouth or have stomach issues that affect medication absorption.

I haven't had any blood or platelet transfusions in the last 28 days.

Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive olaparib 150mg by mouth twice daily for one month, then increased to 300mg twice daily if no grade 3 or greater adverse events occur

6 months

Monthly reassessment for toxicity, radiological scans every 3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Long-term follow-up

Participants are monitored for progression-free survival and adverse events

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib

Trial Overview The trial is testing the oral drug Olaparib in patients with kidney cancer that has spread and contains certain DNA repair gene mutations. It's an open-label Phase II study where all participants receive the medication to see how it affects their cancer.

How Is the Trial Designed?

Group I: Olaparib Experimental Treatment 1 Intervention

Participants with metastatic renal cell carcinoma that harbor an inactivating mutation in BAP-1, ATM, BRCA1, BRCA2, PALB2, CHEK2, BRIP1, RAD51C, BARD1, CDK12, CHEK1, FANCL, PP2R2A, RAD51B, RAD51D, or RAD54L that have had prior treatment with at least one immune checkpoint inhibitor or anti-VEGF therapy with measureable disease on CT imaging according to RECIST 1.1 criteria. Participants will be initially treated with olaparib 150mg by mouth twice daily for one month. After one month of therapy, the dose will be increased to 300mg by mouth twice daily provided there are no grade 3 or greater adverse events experienced. Reassessment will occur at least monthly for toxicity. Radiological scans will be performed every 3 months to assess disease response. Treatment will be continued until clinical and/or radiographic progression according to RECIST 1.1 criteria or unmanageable toxicity requiring cessation.

Olaparib is already approved in European Union, United States for the following indications:

Approved in European Union as Lynparza for:

• Breast cancer
• Ovarian cancer
• Fallopian tube cancer
• Peritoneal cancer
• Pancreatic cancer
• Prostate cancer
• Endometrial cancer

Approved in United States as Lynparza for:

• Ovarian, fallopian tube, and primary peritoneal cancer
• Breast cancer
• Prostate cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

Pazopanib is an FDA-approved multi-kinase inhibitor effective in treating advanced renal cell carcinoma (RCC), showing significant clinical activity in metastatic cases.

The drug not only targets VEGF receptors but also affects other receptors, which contributes to its side-effect profile, indicating a broader mechanism of action beyond just inhibiting VEGF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pazopanib and anti-VEGF therapy. Drabkin, HA.[2021]

Current first-line treatments for metastatic renal cell carcinoma include sunitinib, temsirolimus, pazopanib, and a combination of bevacizumab with interferon α, which target key pathways involved in tumor growth and angiogenesis.

New agents like axitinib, tivozanib, and monoclonal antibodies are being investigated in clinical trials, showing promise for improving survival outcomes in patients who have not responded to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comprehensive overview of targeted therapy in metastatic renal cell carcinoma. Mihaly, Z., Sztupinszki, Z., Surowiak, P., et al.[2021]

In the phase III COMPARZ study, pazopanib showed a numerically shorter median time to response compared to sunitinib (11.9 weeks vs. 17.4 weeks), indicating it may act faster in treating advanced renal cell carcinoma.

Patients who experienced dose modifications due to adverse events had significantly better outcomes, with improved median progression-free survival and overall response rates, suggesting that managing side effects can enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COMPARZ Post Hoc Analysis: Characterizing Pazopanib Responders With Advanced Renal Cell Carcinoma. Sternberg, CN., Motzer, RJ., Hutson, TE., et al.[2021]

In a phase 3 trial involving 1110 patients with metastatic renal cell carcinoma, pazopanib was found to be noninferior to sunitinib in terms of progression-free survival, indicating it is an effective treatment option.

Patients treated with pazopanib experienced a longer quality-adjusted time without symptoms or toxicity (Q-TWiST) compared to those on sunitinib, primarily due to reduced severe toxicity, suggesting pazopanib may offer a better quality of life during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality-adjusted time without symptoms or toxicity analysis of pazopanib versus sunitinib in patients with renal cell carcinoma. Beaumont, JL., Salsman, JM., Diaz, J., et al.[2021]

In a study of 143 patients with advanced renal cell carcinoma (RCC), over 50% of patients remained on pazopanib therapy for nearly 4 months, demonstrating high persistence and compliance across both treatment-naïve and previously treated groups.

Younger age and higher comorbidity were identified as strong predictors of better persistence and compliance with pazopanib treatment, suggesting that these factors may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistence and compliance with pazopanib in patients with advanced renal cell carcinoma within a U.S. administrative claims database. Hackshaw, MD., Nagar, SP., Parks, DC., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03786796

NCT03786796 | Study of Olaparib in Metastatic Renal Cell ... Participants will be initially treated with olaparib 150mg by mouth twice daily for one month. After one month of therapy, the dose will be increased to 300mg ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10445572/

A phase II study of Olaparib in Metastatic Renal Cell ... This is the first study investigating single agent PARPi in RCC with the interim trial analysis indicating promising activity of olaparib in aRCC pts with BAP1 ...

3. kidneycancer.org kidneycancer.org/trial/study-of-olaparib-in-metastatic-renal-cell-carcinoma-patients-with-dna-repair-gene-mutations/

Study of Olaparib in Metastatic Renal Cell Carcinoma ... Single arm, single site, open-label Phase II study of the effects of oral olaparib in participants with metastatic renal cell carcinoma that harbor an ...

4. resources.advancedpractitioner.com resources.advancedpractitioner.com/renal-cell-carcinoma/news/orchid-a-phase-ii-study-of-olaparib-in-metastatic-renal-cell-carcinoma-patients-harboring-a-bap1-or-other-dna-repair-gene-mutations/

Renal Cell Carcinoma This is an interim analysis of the ORCHID study, which is investigating the clinical activity of single agent olaparib in patients with advanced ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8300201/

The Emerging Role of Poly (ADP-Ribose) Polymerase ... Niraparib and talazoparib were the most effective at reducing cell survival, proliferation, and clonogenic ability in vitro.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/208558s014lbl.pdf

LYNPARZA® (olaparib) tablets, for oral use - accessdata.fda.gov The safety of Lynparza was evaluated in gBRCAm patients with HER2-negative metastatic breast cancer who had previously received up to two lines of ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.6_suppl.TPS400

ORCHID: A phase II study of olaparib in metastatic renal ... We have initiated a phase 2 clinical trial to examine the activity of the PAPR inhibitor olaparib in metastatic RCC with BAP-1 and select DNA repair gene ...

8. lynparza.com lynparza.com/

LYNPARZA® (olaparib) - Official Patient Website Find out about LYNPARZA® (olaparib), a targeted treatment for certain types of cancer. See important safety information, downloadable resources and more.