Metastatic MelanomaPhase 2NCT04633902
Phase II Study of Olaparib and Pembrolizumab in Advanced Melanoma With Homologous Recombination (HR) Mutation
A Phase 2 study testing Olaparib and Pembrolizumab in people with Metastatic Melanoma, run by California Pacific Medical Center Research Institute at 2 sites in United States.
Trial summary
This open-label phase II trial studies how well olaparib in combination with pembrolizumab works in treating patients with advanced, metastatic melanoma with the homologous recombination (HR) pathway gene mutation / alteration. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Melanoma
- What is being tested?
- Olaparib and Pembrolizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 41 participants
- Where
- 2 sitesUnited States
- Study dates
- 3 Mar 2021to 31 Dec 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
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
- Histologically confirmed diagnosis of unresectable or metastatic stage III or IV melanoma
- Must have genetic HR mutation/ alteration including ARID1A/B, ARID2, ATM, ATR, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCA, FANCD2, MRN11A, PALB2, RAD50, RAD51, RAD54B
- Disease must be refractory or resistant to anti PD-1 therapy (defined as disease progression within 6 months after the last dose of anti PD-1 antibody therapy) and, for V600 BRAF mutation, disease must be progressed after BRAF inhibitor therapy; or patients could not have tolerated the standard therapies.
- Must have measurable disease based on RECIST 1.1.
- Must have an ECOG performance status of 0 to 1.
- Prior systemic cytotoxic therapy up to 1 regimens is allowed; There is no limit on the number of prior immunotherapy or targeted therapy regimens.
- Must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline.
Who cannot join
- Previously treated with a PARP inhibitor
- Has received prior radiotherapy within 2 weeks of start of study treatment. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
- Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
- Previous solid organ or allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT) for solid tumors.
- Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
- Has active autoimmune disease that has required systemic treatment in the past 2 years
- Has a history of (non-infectious) pneumonitis due to a single agent PD-1 / PD-L1 antibody therapy that required steroids or has current pneumonitis.
Trial locations and contacts
2 sites in 1 country.
United States2 sites, 2 recruiting
- Recruiting
The University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
Debbie Stroughter, 713-792-7734, CR_Study_Registration@mdanderson.org
Sapna Patel, MD
- Recruiting
California Pacific Medical Center Research Institute
San Francisco, California, 94115
About this study
Official title: Phase II Study of Olaparib in Combination With Pembrolizumab in Patients With Advanced Melanoma With Homologous Recombination (HR) Pathway Gene Mutation
This open-label phase II trial studies how well olaparib in combination with pembrolizumab works in treating patients with advanced, metastatic melanoma with the homologous recombination (HR) pathway gene mutation / alteration. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and potentially augment an anti-tumor immune response to pembrolizumab. The trial is designed to assess the efficacy and safety of olaparib in combination with pembrolizumab in patients with HR mutation/ alteration whose disease progressed on prior immunotherapy and/or BRAF-targeting therapy
Read the detailed description
Treatment with PARP inhibitors could represent a novel opportunity to selectively kill a subset of cancer cells with deficiencies in DNA repair pathways. For example, a tumor arising in a patient with a germline BRCA mutation (gBRCAmut) has a defective homologous recombination DNA repair pathway and would be increasingly dependent on NHEJ, alt-NHEJ, and BER for maintenance of genomic integrity. PARP inhibitors block alt-NHEJ and BER, forcing tumors with BRCA deficiencies to use the error-prone NHEJ to fix double-strand breaks. Non-BRCA deficiencies in homologous recombination DNA repair genes could also enhance tumor cell sensitivity to PARP inhibitors. The rationale for anticancer activity in a subset of non-gBRCAmut tumors is that they share distinctive DNA repair defects with gBRCAmut carriers, a phenomenon broadly described as "BRCAness." DNA repair defects can be caused by germline or somatic alterations to the homologous recombination DNA repair pathway. Homologous recombination is a complex pathway, and several genes other than BRCA1 and BRCA2 are required either to sense or repair DNA double-strand breaks via the homologous recombination pathway. Therefore, PARP inhibitors are also selectively cytotoxic for cancer cells with deficiencies in DNA repair proteins other than BRCA1 and BRCA2.
In melanoma, genetic HR mutation/ alterations are rather common. Retrospective data showed that nearly 20-30% of cutaneous melanoma harbors a mutation in at least 1 of the HR genes in their tumor. The commonly altered genes were ARID1A, FANCA, ATM, BRCA1, ATRX and BRCA2, ATR, BRCA1 and BRIP1. These findings indicate that HR mutations / alterations are frequently observed in metastatic melanoma, and they suggest that PARP inhibitors could potentially be of a great clinical value in a substantial portion of the patients with advanced melanoma. In addition, the retrospective data also showed that presence of HR mutation was associated with high TMB and clinical response to checkpoint immunotherapy. Therefore, the investigators propose a phase II study of niraparib in patients with advanced melanoma with genetic homologous recombination mutation/ alteration.
In this clinical study, clinical efficacy of olaparib in combination with pembrolizumab will be evaluated by assessing an objective clinical response rate in patients with advanced, metastatic melanoma with the homologous recombination (HR) pathway gene mutation / alteration. All participating patients will receive olaparib 300 mg a day and pembrolizumab 200 mg every 3 weeks (for up to 2 years) until disease progresses or they experience intolerable toxicity.
- Conditions
- Metastatic Melanoma
- Being tested
- Olaparib, Pembrolizumab
- Keywords
- Homologous recombination (HR), Mutation, Olaparib, Pembrolizumab, PARP inhibitor, anti PD-1 antibody
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OlaparibDrug
Also called Lynparza
Olaparib 300 mg BID daily
PembrolizumabDrug
Also called Keytruda
Pembrolizumab 200 mg IV eveyr 3 weeks (for up to 2 years)
| Study group | Role | What they receive |
|---|---|---|
| Olaparib + Pembrolizumab | Experimental | This arm will enroll patients who has advanced melanoma with a genetic HR mutation/ alteration including mutation/ deletion in ARID1A/B, ARID2, ATM, ATR, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCA, FANCD2, MRN11A, PALB2, RAD50, RAD51, RAD54B. Receives: Drug: Olaparib; Drug: Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective Response Rate (ORR)
ORR of olaparib in combination with pembrolizumab in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration using RECIST v1.1
Measured: 6 months
Secondary outcomes (3)
Progression-free survival (PFS)
PFS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with olaparib in combination with pembrolizumab
Measured: 2 years
Overall survival (OS)
OS of patients with advanced melanoma with genetic HR mutation/ alteration who are treated with olaparib in combination with pembrolizumab
Measured: 2 years
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Evaluation of the safety profile of olaparib in combination with pembrolizumab in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Nov 2020
- Study start3 Mar 2021
- Primary completion30 Jun 2023 (estimated)
- Study completion31 Dec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastatic MelanomaStudies of the same condition, open and under way.
- 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
- 41 participants (estimated)
Sponsor and investigators
- Lead sponsor
- California Pacific Medical Center Research Institute
- Sponsor type
- University, hospital or other
- Collaborators
- M.D. Anderson Cancer Center
- Responsible party
- Sponsor
- Investigators
- Kevin B Kim, MD, Principal investigator, California Pacific Medical Center Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04633902
- Sponsor's protocol ID
- CPMC19-MEL01
- Status last verified
- Dec 2022
- First submitted
- 12 Nov 2020
- Last updated
- 6 Dec 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Study of Olaparib in Combination With Pembrolizumab in Patients With Advanced Melanoma With Homologous Recombination (HR) Pathway Gene Mutation
- ClinicalTrials.gov ID
- NCT04633902
- Acronym / sponsor ID
- CPMC19-MEL01
- Conditions
- Metastatic Melanoma
- Keywords
- Homologous recombination (HR), Mutation, Olaparib, Pembrolizumab, PARP inhibitor, anti PD-1 antibody
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 41 participants (estimated)
- Lead sponsor
- California Pacific Medical Center Research InstituteUniversity, hospital or other
- Collaborators
- M.D. Anderson Cancer Center
- Study start
- 3 Mar 2021 (actual)
- Primary completion
- 30 Jun 2023 (estimated)
- Study completion
- 31 Dec 2024 (estimated)
- First posted
- 18 Nov 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This open-label phase II trial studies how well olaparib in combination with pembrolizumab works in treating patients with advanced, metastatic melanoma with the homologous recombination (HR) pathway gene mutation / alteration. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and potentially augment an anti-tumor immune response to pembrolizumab. The trial is designed to assess the efficacy and safety of olaparib in combination with pembrolizumab in patients with HR mutation/ alteration whose disease progressed on prior immunotherapy and/or BRAF-targeting therapy
Detailed description
Treatment with PARP inhibitors could represent a novel opportunity to selectively kill a subset of cancer cells with deficiencies in DNA repair pathways. For example, a tumor arising in a patient with a germline BRCA mutation (gBRCAmut) has a defective homologous recombination DNA repair pathway and would be increasingly dependent on NHEJ, alt-NHEJ, and BER for maintenance of genomic integrity. PARP inhibitors block alt-NHEJ and BER, forcing tumors with BRCA deficiencies to use the error-prone NHEJ to fix double-strand breaks. Non-BRCA deficiencies in homologous recombination DNA repair genes could also enhance tumor cell sensitivity to PARP inhibitors. The rationale for anticancer activity in a subset of non-gBRCAmut tumors is that they share distinctive DNA repair defects with gBRCAmut carriers, a phenomenon broadly described as "BRCAness." DNA repair defects can be caused by germline or somatic alterations to the homologous recombination DNA repair pathway. Homologous recombination is a complex pathway, and several genes other than BRCA1 and BRCA2 are required either to sense or repair DNA double-strand breaks via the homologous recombination pathway. Therefore, PARP inhibitors are also selectively cytotoxic for cancer cells with deficiencies in DNA repair proteins other than BRCA1 and BRCA2.
In melanoma, genetic HR mutation/ alterations are rather common. Retrospective data showed that nearly 20-30% of cutaneous melanoma harbors a mutation in at least 1 of the HR genes in their tumor. The commonly altered genes were ARID1A, FANCA, ATM, BRCA1, ATRX and BRCA2, ATR, BRCA1 and BRIP1. These findings indicate that HR mutations / alterations are frequently observed in metastatic melanoma, and they suggest that PARP inhibitors could potentially be of a great clinical value in a substantial portion of the patients with advanced melanoma. In addition, the retrospective data also showed that presence of HR mutation was associated with high TMB and clinical response to checkpoint immunotherapy. Therefore, the investigators propose a phase II study of niraparib in patients with advanced melanoma with genetic homologous recombination mutation/ alteration.
In this clinical study, clinical efficacy of olaparib in combination with pembrolizumab will be evaluated by assessing an objective clinical response rate in patients with advanced, metastatic melanoma with the homologous recombination (HR) pathway gene mutation / alteration. All participating patients will receive olaparib 300 mg a day and pembrolizumab 200 mg every 3 weeks (for up to 2 years) until disease progresses or they experience intolerable toxicity.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Olaparib + Pembrolizumab | Experimental | Drug: Olaparib, Drug: PembrolizumabThis arm will enroll patients who has advanced melanoma with a genetic HR mutation/ alteration including mutation/ deletion in ARID1A/B, ARID2, ATM, ATR, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCA, FANCD2, MRN11A, PALB2, RAD50, RAD51, RAD54B. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Histologically confirmed diagnosis of unresectable or metastatic stage III or IV melanoma
- Must have genetic HR mutation/ alteration including ARID1A/B, ARID2, ATM, ATR, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCA, FANCD2, MRN11A, PALB2, RAD50, RAD51, RAD54B
- Disease must be refractory or resistant to anti PD-1 therapy (defined as disease progression within 6 months after the last dose of anti PD-1 antibody therapy) and, for V600 BRAF mutation, disease must be progressed after BRAF inhibitor therapy; or patients could not have tolerated the standard therapies.
- Must have measurable disease based on RECIST 1.1.
- Must have an ECOG performance status of 0 to 1.
Key exclusion criteria (8 listed)
- Previously treated with a PARP inhibitor
- Has received prior radiotherapy within 2 weeks of start of study treatment. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
- Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
- Previous solid organ or allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT) for solid tumors.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| OlaparibAlso: LynparzaOlaparib 300 mg BID daily | Drug | Olaparib + Pembrolizumab |
| PembrolizumabAlso: KeytrudaPembrolizumab 200 mg IV eveyr 3 weeks (for up to 2 years) | Drug | Olaparib + Pembrolizumab |
Primary outcome
Objective Response Rate (ORR)
Time frame: 6 months
ORR of olaparib in combination with pembrolizumab in patients with advanced melanoma with genetic homologous recombination (HR) mutation/ alteration using RECIST v1.1
3 secondary outcomes
Progression-free survival (PFS)
Time frame: 2 years
Overall survival (OS)
Time frame: 2 years
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Time frame: 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Dec 2022.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kevin B Kim, MD principal investigator
California Pacific Medical Center Research Institute
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Olaparib and Pembrolizumab in people with Metastatic Melanoma, run by California Pacific Medical Center Research Institute at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 6 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Kevin B Kim, MD (415-885-8600, ClinicalResearch@sutterhealth.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective Response Rate (ORR) (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Dec 2022.