What side effects are associated with this type of intervention?

Common side effects of CTLA-4 inhibitors (e.g., Quavonlimab) and PD-1 inhibitors (e.g., Pembrolizumab) include immune-related adverse events such as colitis, hepatitis, dermatitis, endocrinopathies (e.g., thyroiditis, hypophysitis), and pneumonitis. These side effects occur because these drugs enhance the immune system's activity, which can lead to inflammation and damage to normal tissues. Severe side effects may require immunosuppressive treatment, such as high-dose glucocorticoids. Patients should be closely monitored for these adverse events during treatment.

What prior FDA approvals exist?

The FDA has approved several treatments involving CTLA-4 and PD-1 inhibitors for solid tumors. Ipilimumab, a CTLA-4 inhibitor, was one of the first to be approved for metastatic melanoma. Pembrolizumab and Nivolumab, both PD-1 inhibitors, have been approved for various solid tumors, including melanoma, non-small cell lung cancer, and renal cell carcinoma. These approvals have paved the way for combination therapies, such as Nivolumab plus Ipilimumab, which have shown efficacy in treating advanced melanoma and other solid tumors.

What other types of research exist?

Promising novel alternatives for solid tumor patients include: 1) Nivolumab plus Ipilimumab, which has shown efficacy in various solid tumors including non-small cell lung cancer and renal cell carcinoma. 2) Atezolizumab combined with chemotherapy, which has demonstrated positive outcomes in non-small cell lung cancer. 3) Cemiplimab plus chemotherapy, which has shown efficacy in non-small cell lung cancer. 4) Tislelizumab plus chemotherapy, which has shown promising results in advanced squamous non-small cell lung cancer. These alternatives offer new avenues for treatment and should be discussed with a healthcare provider.

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Monoclonal Antibodies

Quavonlimab + Pembrolizumab for Advanced Cancer

Q: What is the mechanism of action of this treatment?

Immune checkpoint inhibitors, such as CTLA-4 inhibitors (e.g., Quavonlimab) and PD-1 inhibitors (e.g., Pembrolizumab), work by blocking proteins that downregulate the immune response. CTLA-4 inhibitors prevent CTLA-4 from binding to its ligands (CD80/CD86), thereby enhancing T-cell activation and proliferation. PD-1 inhibitors block the interaction between PD-1 on T cells and its ligands (PD-L1/PD-L2) on tumor cells, preventing the 'off' signal that allows cancer cells to evade immune detection. These mechanisms are crucial for solid tumor patients as they help the immune system recognize and attack cancer cells more effectively, potentially leading to better clinical outcomes.

Phase 1 & 2

Waitlist Available

Research Sponsored by Merck Sharp & Dohme Corp.

Eligibility Criteria Checklist

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

Must have

For Dose Confirmation Phase SCLC Arm (Arm D): Have histologically- or cytologically-confirmed metastatic (Stage III/IV) SCLC with progressive disease after ≥1 platinum-based chemotherapy regimen. Participants with platinum-sensitive disease are eligible. Have measurable disease by RECIST 1.1 as assessed by the local site investigator/radiology. Have Eastern Cooperative Oncology Group (ECOG) Performance Scale status of 0 or 1. A female participant is eligible to participate if she is not pregnant or breastfeeding and at least 1 of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR Is a WOCBP and using a contraceptive method that is highly effective during the intervention period and for at least 120 days after the last dose of pembrolizumab or pembrolizumab/quavonlimab, whichever comes last. Female participants of childbearing potential must have negative urine or serum pregnancy test within 24 hours for urine and within 72 hours for serum prior to receiving the first dose of study treatment. Male participants with a female partner(s) of child-bearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication and refrain from donating sperm during this period. Must submit an evaluable baseline tumor sample for analysis (either a recent or archival tumor sample)

For Efficacy Expansion Phase Arms F and G: Have histologically/cytologically-confirmed unresectable Stage III or Stage IV melanoma per American Joint Committee on Cancer (AJCC) staging system version 8, not amenable to local therapy. Have at least 1 measurable lesion by CT or MRI per RECIST 1.1 by BICR. Cutaneous lesions and other superficial lesions are not considered measurable lesions for the purposes of this protocol, but may be considered as non-target lesions. Participants with unresectable Stage III or IV disease must have progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies (combinations with anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4] agents will not be allowed). Participants who receive anti-PD-1 therapy as adjuvant treatment following complete resection of Stage III or IV melanoma and have disease recurrence (unresectable loco-regional disease or distant metastases) while on active treatment or within 6 months of stopping anti-PD-1 are eligible. Have submitted pre-trial imaging and provided a baseline tumor sample. Proto-oncogene B-raf (BRAF) V600 mutation-positive melanoma participants should have received targeted therapy for advanced or metastatic disease (eg, BRAF/MEK inhibitor, alone or in combination) prior to enrolling on this study; however, they are not required to progress on this treatment prior to enrollment. BRAF V600E mutation-positive melanoma participants who have NOT received a BRAF inhibitor (either as adjuvant therapy or in the metastatic disease setting) with lactate dehydrogenase (LDH) < local upper limit of normal (ULN), no clinically significant tumor-related symptoms, and absence of rapidly progressing metastatic melanoma. Approximately 10 participants each from Arms F and G will have 2 mandatory biopsies

Must not have

For Dose Escalation Cohorts (1-3) and Dose Confirmation Arms (A-E): Has known untreated central nervous system (CNS) metastases. Has known carcinomatous meningitis. Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse events (irAE). Has had a severe hypersensitivity reaction to treatment with any monoclonal antibody or components of the study drug. Has any active infection requiring therapy. Has a history of interstitial lung disease, history of noninfectious pneumonitis that required steroids (or has current pneumonitis), or history of inflammatory bowel disease. Has an active autoimmune disease that has required systemic treatment in the past 2 years. Has clinically significant cardiac disease. Has received a live or live attenuated vaccine within 28 days of planned treatment start. Has known history of human immunodeficiency virus (HIV) and/or known active Hepatitis B or C infections, and/or known to be positive for hepatitis B surface antigen (HBsAg)/ hepatitis B virus (HBV) DNA. Has known psychiatric or substance abuse disorders that would interfere with the participant's ability to cooperate with the requirements of the trial. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with screening and for up to 120 days following cessation of pembrolizumab or pembrolizumab/quavonlimab. Has not fully recovered from any effects of major surgery without significant detectable infection

For all phases of the study: Has received previous treatment with another agent targeting cytotoxic T lymphocyte leukocyte antigen (CTLA)-4

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to ~2.5 years

Awards & highlights

Summary

This trial is testing a new drug called quavonlimab combined with pembrolizumab in patients with advanced cancers. Pembrolizumab is a medication that has shown effectiveness in treating various cancers and has been approved for multiple uses. The goal is to determine if these drugs can help the immune system fight cancer cells more effectively.

Who is the study for?

This trial is for adults with advanced solid tumors. Participants must have measurable disease, be in good physical condition (ECOG status of 0 or 1), and not pregnant or breastfeeding. They should have tried all other treatments without success, agree to use contraception, and provide a tumor sample. Certain types of cancer patients are excluded, like those with untreated brain metastases or active infections.

What is being tested?

The study tests escalating doses of Quavonlimab combined with Pembrolizumab on participants with advanced solid tumors to evaluate safety, tolerability, how the body processes the drugs (pharmacokinetics), and initial effectiveness against the tumors.

What are the potential side effects?

Potential side effects include reactions at the injection site, flu-like symptoms such as fever and chills, fatigue, nausea, skin reactions, risk of infection due to immune system suppression; organ inflammation; hormonal gland problems leading to changes in mood or behavior.

Eligibility Criteria

Inclusion Criteria

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

Exclusion Criteria

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

Select...

I have been treated with a drug targeting CTLA-4 before.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to ~2.5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to ~2.5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to ~2.5 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

Coformulation: Number of participants discontinuing study treatment due to an AE

Coformulation: Number of participants with ≥1 AE

Coformulation: Number of participants with ≥1 DLT

+6 more

Secondary study objectives

AUC of quavonlimab

Area under the plasma concentration time curve (AUC) of pembrolizumab

Chinese Cohort: AUC of pembrolizumab

+15 more

Trial Design

12Treatment groups

Experimental Treatment

Group I: Expansion: DL1 Quavonlimab Schedule 2+PDL2 Pembro Schedule 2: Arm FExperimental Treatment2 Interventions

On Cycle 1, Day 1 of the Efficacy Expansion Phase and during all subsequent cycles, participants with PD-1/PD-L1 refractory melanoma receive quavonlimab at DL1 in combination with pembrolizumab at pembrolizumab dose level 2 (PDL2). Both quavonlimab and pembrolizumab will be administered according to Schedule 2 for up to 24 months on study.

Group II: Expansion: DL1 Quavonlimab Schedule 2 Monotherapy: Arm GExperimental Treatment1 Intervention

On Cycle 1, Day 1 of the Efficacy Expansion Phase and during all subsequent cycles, participants with PD-1/PD-L1 refractory melanoma receive quavonlimab at DL1 according to Schedule 2 for up to 24 months on study. Participants who demonstrate radiographically confirmed progressive disease in Arm G will be eligible to receive combination therapy with pembrolizumab (crossover).

Group III: Escalation: Dose Level (DL) 1 Quavonlimab + Pembro: Cohort 1Experimental Treatment2 Interventions

On Cycle 1, Day 1 of the Dose Escalation Phase, advanced solid tumor participants receive a single monotherapy dose lead-in with quavonlimab at dose level 1 (DL1). On Cycle 2, Day 1, and for 3 subsequent cycles on Day 1 (Cycles 3 to 5), these participants receive quavonlimab at DL1 in combination with pembrolizumab (pembro) at pembrolizumab dose level 1 (PDL1) according to Schedule 1. For all subsequent cycles (starting with Cycle 6), all participants receive pembrolizumab monotherapy according to Schedule 1. Participants will be treated for up to 35 cycles total on study.

Group IV: Escalation: DL 3 Quavonlimab + Pembro: Cohort 3Experimental Treatment2 Interventions

On Cycle 1, Day 1 of the Dose Escalation Phase, participants with advanced solid tumors except NSCLC receive a single monotherapy dose lead-in with quavonlimab at DL3. On Cycle 2, Day 1, and for 3 subsequent cycles on Day 1 (Cycles 3 to 5), these participants receive quavonlimab at DL3 in combination with pembrolizumab at PDL1 according to Schedule 1. For all subsequent cycles (starting with Cycle 6), all participants receive pembrolizumab monotherapy according to Schedule 1. Participants will be treated for up to 35 cycles total on study.

Group V: Escalation: DL 2 Quavonlimab + Pembro: Cohort 2Experimental Treatment2 Interventions

On Cycle 1, Day 1 of the Dose Escalation Phase, participants with advanced solid tumors except NSCLC receive a single monotherapy dose lead-in with quavonlimab at DL2. On Cycle 2, Day 1, and for 3 subsequent cycles on Day 1 (Cycles 3 to 5), these participants receive quavonlimab at DL2 in combination with pembrolizumab at PDL1 according to Schedule 1. For all subsequent cycles (starting with Cycle 6), all participants receive pembrolizumab monotherapy according to Schedule 1. Participants will be treated for up to 35 cycles total on study.

Group VI: Confirmation: DL 2 Quavonlimab Schedule 2 + Pembro (SCLC): Arm DExperimental Treatment2 Interventions

On Cycle 1, Day 1 of the Dose Confirmation Phase, participants with SCLC receive quavonlimab at DL2 in combination with pembrolizumab at PDL1. On all subsequent cycles, participants receive pembrolizumab at PDL1 according to Schedule 1 and quavonlimab at DL2 according to Schedule 2. Participants will be treated for up to 35 cycles total on study.

Group VII: Confirmation: DL 2 Quavonlimab Schedule 2 + Pembro (NSCLC): Arm CExperimental Treatment2 Interventions

On Cycle 1, Day 1 of the Dose Confirmation Phase, participants with NSCLC receive quavonlimab at DL2 in combination with pembrolizumab at PDL1. On all subsequent cycles, participants receive pembrolizumab at PDL1 according to Schedule 1 and at DL2 quavonlimab according to Schedule 2. Participants will be treated for up to 35 cycles total on study.

Group VIII: Confirmation: DL 2 Quavonlimab Schedule 1 + Pembro (NSCLC): Arm EExperimental Treatment2 Interventions

On Cycle 1, Day 1 of the Dose Confirmation Phase and during all subsequent cycles, participants with NSCLC receive quavonlimab at DL2 in combination with pembrolizumab at PDL1 according to Schedule 1. Participants will be treated for up to 35 cycles total on study.

Group IX: Confirmation: DL 1 Quavonlimab Schedule 2 + Pembro (NSCLC): Arm BExperimental Treatment2 Interventions

On Cycle 1, Day 1 of the Dose Confirmation Phase, participants with NSCLC receive quavonlimab at DL1 in combination with pembrolizumab at PDL1. On all subsequent cycles, participants receive pembrolizumab at PDL1 according to Schedule 1 and quavonlimab at DL1 according to Schedule 2. Participants will be treated for up to 35 cycles total on study.

Group X: Confirmation: DL 1 Quavonlimab Schedule 1 + Pembro (NSCLC): Arm AExperimental Treatment2 Interventions

On Cycle 1, Day 1 of the Dose Confirmation Phase and during all subsequent cycles, participants with NSCLC receive quavonlimab at DL1 in combination with pembrolizumab at PDL1, both according to Schedule 1. Participants will be treated for up to 35 cycles total on study.

Group XI: Coformulation: Pembrolizumab/Quavonlimab Schedule 2: Arm IExperimental Treatment1 Intervention

On Cycle 1, Day 1 of the Coformulation Phase and during all subsequent cycles, participants with advanced/metastatic solid tumors receive pembrolizumab/quavonlimab according to Schedule 2 for up to 24 months on study.

Group XII: Coformulation Phase in China: Pembrolizumab/Quavonlimab Schedule 2: Arm KExperimental Treatment1 Intervention

On Cycle 1, Day 1 of the Coformulation Phase and during all subsequent cycles, participants in mainland China with advanced solid tumors receive pembrolizumab/quavonlimab according to Schedule 2 for up to 24 months on study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Quavonlimab

2017

Completed Phase 2

~420

Pembrolizumab

2017

Completed Phase 2

~2070

Pembrolizumab/Quavonlimab

2017

Completed Phase 2

~420

0 / 4Eligibility 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

Immune checkpoint inhibitors, such as CTLA-4 inhibitors (e.g., Quavonlimab) and PD-1 inhibitors (e.g., Pembrolizumab), work by blocking proteins that downregulate the immune response. CTLA-4 inhibitors prevent CTLA-4 from binding to its ligands (CD80/CD86), thereby enhancing T-cell activation and proliferation. PD-1 inhibitors block the interaction between PD-1 on T cells and its ligands (PD-L1/PD-L2) on tumor cells, preventing the 'off' signal that allows cancer cells to evade immune detection. These mechanisms are crucial for solid tumor patients as they help the immune system recognize and attack cancer cells more effectively, potentially leading to better clinical outcomes.

Recurrent glioma clinical trial, CheckMate-143: the game is not over yet.