ccRCC, Clear Cell RCC, Clear Cell Renal Cell Carcinoma, VHL, VHL Gene Inactivation, VHL Gene Mutation, VHL Syndrome, Von Hippel, Von Hippel-Lindau Disease, Von Hippel-Lindau Syndrome, Modifiers of, Von Hippel's Disease
Conditions
Brief summary
The primary objective of this study is to assess the overall response rate (ORR) of von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC) tumors in VHL participants treated with MK-3795.
Detailed description
This open-label Phase 2 study will evaluate the efficacy, safety, PK, and PD of MK-3795 in participants with VHL disease who have at least 1 measurable VHL disease-associated ccRCC tumor (as defined by RECIST 1.1). MK-3795 will be administered orally and treatment will be continuous. Changes in VHL disease-associated non-ccRCC tumors will also be evaluated.
Interventions
DRUGMK-3795
800 mg twice daily (four 200 mg oral tablets twice daily)
Sponsors
National Institutes of Health (NIH)
Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is an open-label Phase 2 study that will be conducted with a 2-stage design.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has at least 1 measurable ccRCC tumor and no solid ccRCC tumor greater than 3.0 cm, based on radiologic diagnosis (histologic diagnosis not required); may have VHL disease-associated lesions in other organ systems * Has a diagnosis of von Hippel Lindau disease, based on a germline VHL alteration
Exclusion criteria
* Has had prior radiotherapy or systemic anti cancer therapy for ccRCC (includes anti-vascular endothelial growth factor (VEGF) therapy or any systemic investigational anti cancer agent) * Has a prior or concomitant non-VHL disease-associated invasive malignancy with the exception of adequately treated basal or squamous cell carcinoma of the skin, cervical carcinoma in situ or any other malignancy from which the participant has remained disease free for more than 2 years * Has any history of metastatic disease * Has had radiotherapy to any non-ccRCC site within 4 weeks prior to entering the study or has not recovered from adverse events (AE) * Has had any surgical procedure for VHL disease or any major surgical procedure completed within 4 weeks prior to entering the study or has any surgical lesions from recent major surgical procedures that are not well healed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) in VHL Disease-Associated ccRCC Tumors | Up to approximately 76 months | ORR was defined as the percentage of participants in the analysis population who have a best confirmed response of Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). ORR was assessed by independent review committee (ICR) for the primary analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) in VHL Disease-Associated ccRCC Tumors | Up to approximately 76 months | DOR was defined as the interval from the first documented evidence of a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 until PD or death due to any cause, whichever occurs first, in participants demonstrating a best confirmed response of CR or PR. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. |
| Time to Response (TTR) in VHL Disease-Associated ccRCC Tumors | Up to approximately 76 months | TTR was defined as the interval from the start of study treatment to the first documentation of a response per RECIST 1.1, and calculated for participants with a best confirmed response of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions). |
| Overall Response Rate (ORR) in VHL Disease-Associated Non-ccRCC Tumors | Up to approximately 76 months | ORR was defined as the percentage of participants in the analysis population who have a best confirmed response of Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). |
| Progression-free Survival (PFS) in VHL Disease-Associated Non-ccRCC Tumors | Up to approximately 76 months | PFS was defined as the interval from the start of study treatment to the first documented PD or death from any cause, whichever occurs first. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. |
| Duration of Response (DOR) in VHL Disease-Associated Non-ccRCC Tumors | Up to approximately 76 months | DOR was defined as the interval from the first documented evidence of a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 until Progressive Disease (PD) or death due to any cause, whichever occurs first, in participants demonstrating a best confirmed response of CR or PR. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. |
| Progression-free Survival (PFS) in VHL Disease-Associated ccRCC Tumors | Up to approximately 76 months | PFS was defined as the interval from the start of study treatment to the first documented Progressive Disease (PD) or death from any cause, whichever occurs first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. |
| MK-3795 Plasma Concentration | Week 1: pre-dose and 6 hours post-dose, Week 3, 5, 9, 13, and 17: pre-dose | Blood samples for the determination of MK-3795 concentration were collected at pre-specified timepoints before and after administration of study intervention. |
| MK-3795 Metabolite Plasma Concentration | Week 1: pre-dose and 6 hours post-dose, Week 3, 5, 9, 13, and 17: pre-dose | Blood samples for the determination of MK-3795 metabolite concentration were collected at pre-specified timepoints before and after administration of study intervention. |
| Number of Participants Who Experienced One or More Adverse Events (AEs) | Up to approximately 76 months | An AE was defined as any untoward medical occurrence in a participant regardless of its causal relationship to study treatment. An AE can be any unfavorable and unintended sign (including any clinically significant abnormal laboratory test result), symptom, or disease temporally associated with the use of the study drug, whether or not it was considered to be study drug related. |
| Number of Participants Who Discontinued Study Intervention Due to an AE | Up to approximately 74 months | An AE was defined as any untoward medical occurrence in a participant regardless of its causal relationship to study treatment. An AE can be any unfavorable and unintended sign (including any clinically significant abnormal laboratory test result), symptom, or disease temporally associated with the use of the study drug, whether or not it is considered to be study drug related. |
| Time to Response (TTR) in VHL Disease-Associated Non-ccRCC Tumors | Up to approximately 76 months | TTR was defined as the interval from the start of study treatment to the first documentation of a response per RECIST 1.1, and calculated for participants with a best confirmed response of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MK-3795 Participants received 800 mg MK-3795 orally twice daily. Participants continued to receive MK-3795 in the absence of unacceptable treatment related toxicity or unequivocal disease progression. | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | MK-3795 |
|---|---|
| Age, Continuous | 58.3 Years STANDARD_DEVIATION 8.14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 4 |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 3 / 4 |
Outcome results
Primary
Overall Response Rate (ORR) in VHL Disease-Associated ccRCC Tumors
ORR was defined as the percentage of participants in the analysis population who have a best confirmed response of Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). ORR was assessed by independent review committee (ICR) for the primary analysis.
Time frame: Up to approximately 76 months
Population: The analysis population consisted of all allocated participants who received at least one dose of study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-3795 | Overall Response Rate (ORR) in VHL Disease-Associated ccRCC Tumors | 0.0 Percentage of Participants |
Secondary
Duration of Response (DOR) in VHL Disease-Associated ccRCC Tumors
DOR was defined as the interval from the first documented evidence of a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 until PD or death due to any cause, whichever occurs first, in participants demonstrating a best confirmed response of CR or PR. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.
Time frame: Up to approximately 76 months
Population: The analysis population consisted of all allocated participants who received at least one dose of study intervention and experienced CR or PR. No participants experienced CR or PR and DOR was not analyzed.
Secondary
Duration of Response (DOR) in VHL Disease-Associated Non-ccRCC Tumors
DOR was defined as the interval from the first documented evidence of a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 until Progressive Disease (PD) or death due to any cause, whichever occurs first, in participants demonstrating a best confirmed response of CR or PR. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.
Time frame: Up to approximately 76 months
Population: There were no reported non-ccRCC tumors in allocated participants, therefore no analysis was performed.
Secondary
MK-3795 Metabolite Plasma Concentration
Blood samples for the determination of MK-3795 metabolite concentration were collected at pre-specified timepoints before and after administration of study intervention.
Time frame: Week 1: pre-dose and 6 hours post-dose, Week 3, 5, 9, 13, and 17: pre-dose
Population: The analysis population consisted of all allocated participants who received at least one dose of study intervention and had available MK-3475 metabolite plasma concentration data at the specified timepoints. No participants had available MK-3475 metabolite plasma concentration data at Week 17.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-3795 | MK-3795 Metabolite Plasma Concentration | Week 5 Pre-dose | 3440 ng/mL | Geometric Coefficient of Variation 62.9 |
| MK-3795 | MK-3795 Metabolite Plasma Concentration | Week 9 Pre-dose | 5790 ng/mL | — |
| MK-3795 | MK-3795 Metabolite Plasma Concentration | Week 1 Pre-dose | NA ng/mL | — |
| MK-3795 | MK-3795 Metabolite Plasma Concentration | Week 1 6 Hours Post-dose | 2790 ng/mL | Geometric Coefficient of Variation 95.5 |
| MK-3795 | MK-3795 Metabolite Plasma Concentration | Week 3 Pre-dose | 4530 ng/mL | Geometric Coefficient of Variation 53.7 |
| MK-3795 | MK-3795 Metabolite Plasma Concentration | Week 13 Pre-dose | 6360 ng/mL | — |
Secondary
MK-3795 Plasma Concentration
Blood samples for the determination of MK-3795 concentration were collected at pre-specified timepoints before and after administration of study intervention.
Time frame: Week 1: pre-dose and 6 hours post-dose, Week 3, 5, 9, 13, and 17: pre-dose
Population: The analysis population consisted of all allocated participants who received at least one dose of study intervention and had available MK-3475 plasma concentration data at the specified timepoints. No participants had available MK-3475 plasma concentration data at Week 17.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-3795 | MK-3795 Plasma Concentration | Week 1 Pre-dose | NA ng/mL | — |
| MK-3795 | MK-3795 Plasma Concentration | Week 1 6 Hours Post-dose | 583 ng/mL | Geometric Coefficient of Variation 104.6 |
| MK-3795 | MK-3795 Plasma Concentration | Week 3 Pre-dose | 1750 ng/mL | Geometric Coefficient of Variation 76.8 |
| MK-3795 | MK-3795 Plasma Concentration | Week 5 Pre-dose | 1480 ng/mL | Geometric Coefficient of Variation 93.5 |
| MK-3795 | MK-3795 Plasma Concentration | Week 9 Pre-dose | 2550 ng/mL | — |
| MK-3795 | MK-3795 Plasma Concentration | Week 13 Pre-dose | 3150 ng/mL | — |
Secondary
Number of Participants Who Discontinued Study Intervention Due to an AE
An AE was defined as any untoward medical occurrence in a participant regardless of its causal relationship to study treatment. An AE can be any unfavorable and unintended sign (including any clinically significant abnormal laboratory test result), symptom, or disease temporally associated with the use of the study drug, whether or not it is considered to be study drug related.
Time frame: Up to approximately 74 months
Population: The analysis population consisted of all allocated participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-3795 | Number of Participants Who Discontinued Study Intervention Due to an AE | 2 Participants |
Secondary
Number of Participants Who Experienced One or More Adverse Events (AEs)
An AE was defined as any untoward medical occurrence in a participant regardless of its causal relationship to study treatment. An AE can be any unfavorable and unintended sign (including any clinically significant abnormal laboratory test result), symptom, or disease temporally associated with the use of the study drug, whether or not it was considered to be study drug related.
Time frame: Up to approximately 76 months
Population: The analysis population consisted of all allocated participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-3795 | Number of Participants Who Experienced One or More Adverse Events (AEs) | 4 Participants |
Secondary
Overall Response Rate (ORR) in VHL Disease-Associated Non-ccRCC Tumors
ORR was defined as the percentage of participants in the analysis population who have a best confirmed response of Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
Time frame: Up to approximately 76 months
Population: There were no reported non-ccRCC tumors in allocated participants, therefore no analysis was performed.
Secondary
Progression-free Survival (PFS) in VHL Disease-Associated ccRCC Tumors
PFS was defined as the interval from the start of study treatment to the first documented Progressive Disease (PD) or death from any cause, whichever occurs first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.
Time frame: Up to approximately 76 months
Population: The analysis population consisted of all allocated participants who received at least one dose of study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MK-3795 | Progression-free Survival (PFS) in VHL Disease-Associated ccRCC Tumors | NA Months |
Secondary
Progression-free Survival (PFS) in VHL Disease-Associated Non-ccRCC Tumors
PFS was defined as the interval from the start of study treatment to the first documented PD or death from any cause, whichever occurs first. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD.
Time frame: Up to approximately 76 months
Population: There were no reported non-ccRCC tumors in allocated participants, therefore no analysis was performed.
Secondary
Time to Response (TTR) in VHL Disease-Associated ccRCC Tumors
TTR was defined as the interval from the start of study treatment to the first documentation of a response per RECIST 1.1, and calculated for participants with a best confirmed response of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions).
Time frame: Up to approximately 76 months
Population: The analysis population consisted of all allocated participants who received at least one dose of study intervention and experienced CR or PR. No participants experienced CR or PR and TTR was not analyzed.
Secondary
Time to Response (TTR) in VHL Disease-Associated Non-ccRCC Tumors
TTR was defined as the interval from the start of study treatment to the first documentation of a response per RECIST 1.1, and calculated for participants with a best confirmed response of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions).
Time frame: Up to approximately 76 months
Population: There were no reported non-ccRCC tumors in allocated participants, therefore no analysis was performed.