Clinical trial NCT03179436: Study of Quavonlimab (MK-1308) in Combination With Pembrolizumab (MK-3475) in Advanced Solid Tumors (MK-1308-001)
Official title: A Phase 1 / 2 Open Label, Multi-Arm, Multicenter Study of MK-1308 in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumors
Keywords: Programmed Cell Death Protein 1 (PD-1, PD1),
Programmed Cell Death Ligand 1 (PD-L1, PDL1)
Programmed Cell Death Ligand 2 (PD-L2, PDL2)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2017-06-07
Enrollment: 415
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of escalating doses of quavonlimab when used in combination with pembrolizumab in participants with advanced solid tumors.

Detailed description: After screening, participants will be assigned to the Dose Escalation, Dose Confirmation, Efficacy Expansion, or Coformulation Phase. The Dose Escalation Phase will evaluate available PK and safety data including dose limiting toxicities (DLTs). The Dose Confirmation Phase will gather additional safety, tolerability, PK, and preliminary efficacy data of quavonlimab in combination with pembrolizumab, and will include first-line advanced/metastatic non-small cell lung cancer (NSCLC) and second line (and beyond) advanced/metastatic small cell lung cancer (SCLC). The purpose of the Efficacy Expansion Phase is to gather preliminary anti-tumor efficacy data for quavonlimab in combination with pembrolizumab as well as for quavonlimab monotherapy in the specific target population of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) refractory melanoma. The Coformulation Phase will evaluate the safety and PK of a coformulated product of pembrolizumab/quavonlimab (MK-1308A) in comparison to that of the single, co-administered products given at the same dose and schedule, and include participants with advanced solid tumors and participants from mainland China.

Eligibility criteria: Inclusion Criteria:

For Dose Escalation Phase:

* Have any histologically- or cytologically-confirmed advanced/metastatic solid tumor (except NSCLC for Cohorts 2 and 3) by pathology report and have received, been intolerant to, been ineligible for, or refused all treatment known to confer clinical benefit

For Dose Confirmation Phase NSCLC Arms (A, B, C, and E):

* Have newly diagnosed histologically or cytologically-confirmed stage IIIB/stage IV NSCLC. Epidermal growth factor receptor (EGFR)-and anaplastic lymphoma kinase (ALK) translocation-directed therapy is not indicated as primary therapy. Participant must not have received prior systemic treatment for advanced NSCLC or must have received previous neoadjuvant and adjuvant chemotherapies ≥6 months before dosing of study drug if prior systemic treatment was given for early stage disease

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 child bearing 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

For Dose Coformulation Phase Arm I:

* Have any histologically- or cytologically-confirmed advanced/metastatic solid tumor by pathology report and have received, been intolerant to, been ineligible for or refused all treatment known to confer clinical benefit
* Meet all requirements for Dose Escalation Phase and Dose Confirmation Phase

For the Coformulation Phase - Arm K (China only):

* Have any histologically- or cytologically-confirmed advanced/metastatic solid tumor by pathology report and have received, been intolerant to, been ineligible for, or refused all treatment known to confer clinical benefit
* Be a Chinese participant residing in China.

Exclusion Criteria:

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

For Dose Confirmation Phase:

* Has received previous treatment with another agent targeting programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
* Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to the first dose of study therapy, or has not recovered to Common Toxicity Criteria for Adverse Events (CTCAE) Grade 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier
* Has received lung radiation therapy of \>30 Gray (Gy) within 6 months before the first dose of study treatment
* Is currently participating and receiving study therapy in a study of an investigational agent or has participated and received study therapy in a study of an investigational agent or has used an investigational device within 28 days of administration of quavonlimab.
* Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years

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 Arm F and G (Efficacy Expansion Phase) and Arm K (Coformulation Phase) ONLY:

* Has known active CNS metastases and/or carcinomatous meningitis
* Has not had resolution of anti-PD-1 antibody-related AEs, including immune-mediated AEs back to Grade ≤1 or baseline (not applicable to Arm K)
* Has not discontinued steroid treatment for an irAE for at least 2 weeks prior to the first dose of study drug (not applicable to Arm K)
* Has ocular melanoma (not applicable to Arm K)
* Has mucosal melanoma (not applicable to Arm K)
* Has had an allogenic tissue/solid organ transplant

Primary outcomes:
measure: Percentage of Participants With ≥1 Dose Limiting Toxicity (DLT)
timeFrame: Up to 6 weeks
measure: Number of Participants With ≥1 Adverse Event (AE)
timeFrame: Up to approximately 77 months
measure: Number of Participants Discontinuing Study Treatment Due to an AE
timeFrame: Up to approximately 26 months
measure: Efficacy Expansion: Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) Based on Adjusted Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
timeFrame: Up to approximately 72 months
Secondary outcomes:
measure: Area Under the Plasma Concentration Time Curve (AUC) of Pembrolizumab
timeFrame: At designated time points up to - Cohorts 1-3: Day 15 Cycle 3, Arms A, B, C, D, E: Day 15 Cycle 3, Arm F: Day 21 Cycle 3, Arm I: Day 21 Cycle 3, Arm K: Day 21 Cycle 3. Each cycle is 21 days.
measure: Maximum Concentration (Cmax) of Pembrolizumab
timeFrame: At designated time points up to - Cohorts 1-3: Day 15 Cycle 3, Arms A, B, C, D, E: Day 15 Cycle 3, Arm F: Day 21 Cycle 3, Arm I: Day 21 Cycle 3, Arm K: Day 21 Cycle 3. Each cycle is 21 days.
measure: Minimum Concentration (Cmin) of Pembrolizumab
timeFrame: At designated time points up to - Cohorts 1-3: Day 1 Cycle 4, Arms A, B, C, D, E: Day 15 Cycle 3, Arm F: Day 21 Cycle 3, Arm I: Day 21 Cycle 3, Arm K: Day 21 Cycle 3. Each cycle is 21 days.
measure: Area Under the Plasma Concentration Time Curve (AUC) of Quavonlimab (MK-1308)
timeFrame: At designated time points up to - Cohorts 1-3: Day 15 Cycle 3, Arms A, B, C, D, E: Day 15 Cycle 3, Arm F, G, I: Day 21 Cycle 3, Arm K: Day 21 Cycle 3. Each cycle is 21 days.
measure: Maximum Concentration (Cmax) of Quavonlimab
timeFrame: At designated time points up to - Cohorts 1-3: Day 15 Cycle 3, Arms A, B, C, D, E: Day 15 Cycle 3, Arm F, G, I: Day 21 Cycle 3, Arm K: Day 21 Cycle 3. Each cycle is 21 days.
measure: Minimum Concentration (Cmin) of Quavonlimab
timeFrame: At designated time points up to - Cohorts 1-3: Day 15 Cycle 3, Arms A, B, C, D, E: Day 15 Cycle 3, Arm F, G, I: Day 21 Cycle 3, Arm K: Day 21 Cycle 3. Each cycle is 21 days.
measure: Number of Participants With Pembrolizumab Anti-drug Antibodies (ADAs)
timeFrame: Cohorts 1-3: Predose and day 1 of cycles 2, 3, 5, 6, 7, 9 and every 4 cycles up to 35 cycles. Arms A-E: Predose and day 1 of cycles 1-5, 6, 8 and every 4 cycles up to 35 cycles. Arms F, I, K: Predose and day 1 of cycles 1, 2, 3, 4. Each cycle is 21 days.
measure: Number of Participants With Quavonlimab Anti-drug Antibodies (ADAs)
timeFrame: Cohort 1-3: Predose and day 1 of cycles 2, 3, 5, 6, 7, 9 and every 4 cycles up to 35 cycles. Arms A-E: Predose and day 1 of cycle 1-5, 6, 8 and every 4 cycles up to 35 cycles. Arms F, G, I, K: Predose and day 1 of cycles 1, 2, 3, 4. Each cycle is 21 days.
measure: Dose Escalation, Dose Confirmation, Coformulation: ORR as Assessed by Investigator Based on Adjusted RECIST v1.1
timeFrame: Up to approximately 72 months
measure: Efficacy Expansion: Duration of Response (DOR) as Assessed by BICR Based on Adjusted RECIST v1.1
timeFrame: Up to approximately 72 months
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center ( Site 0013)
state: Arizona
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center ( Site 0005)
state: New Jersey
city: Nashville
country: United States
facility: Tennessee Oncology Nashville ( Site 0004)
state: Tennessee
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics, LLC (START) ( Site 0001)
state: Texas
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute ( Site 1001)
state: Virginia
city: Blacktown
country: Australia
facility: Blacktown Hospital. Western Sydney local health district ( Site 0009)
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle ( Site 0025)
state: New South Wales
city: Wollstonecraft
country: Australia
facility: Melanoma Institute Australia ( Site 0017)
state: New South Wales
city: Brisbane
country: Australia
facility: Gallipoli Medical Research Foundation-GMRF CTU ( Site 0019)
state: Queensland
city: Cairns
country: Australia
facility: Cairns and Hinterland Hospital and Health Service ( Site 0020)
state: Queensland
city: Kurralta Park
country: Australia
facility: Ashford Cancer Centre Research ( Site 0012)
state: South Australia
city: Ballarat
country: Australia
facility: Ballarat Health Services ( Site 0022)
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Health ( Site 0018)
state: Victoria
city: Toronto
country: Canada
facility: Sunnybrook Research Institute ( Site 1103)
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 1104)
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier de l Universite de Montreal - CHUM ( Site 1102)
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital ( Site 1105)
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Centre ( Site 1101)
state: Quebec
city: Santiago
country: Chile
facility: Fundacion Arturo Lopez Perez ( Site 5601)
state: Region M. De Santiago
city: Beijing
country: China
facility: Beijing Cancer hospital-Digestive Oncology ( Site 5001)
state: Beijing
city: Chongqing
country: China
facility: Chongqing Cancer Hospital-Phase 1 Unite ( Site 5004)
state: Chongqing
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital-Medical Oncology ( Site 5003)
state: Zhejiang
city: Marseille
country: France
facility: Hopital La Timone ( Site 3303)
state: Bouches-du-Rhone
city: Bordeaux
country: France
facility: Institut Bergonie ( Site 3306)
state: Gironde
city: Lille
country: France
facility: CHRU Lille - Hopital Claude Huriez ( Site 3302)
state: Nord
city: Pierre Benite
country: France
facility: CH Lyon Sud Hospices Civils de Lyon ( Site 3307)
state: Rhone
city: Villejuif
country: France
facility: Gustave Roussy ( Site 3305)
state: Val-de-Marne
city: Athens
country: Greece
facility: Regional General Hospital of Athens "Laiko" ( Site 3001)
state: Attiki
city: Haifa
country: Israel
facility: Rambam Medical Center ( Site 0003)
city: Jerusalem
country: Israel
facility: Hadassah Ein Karem Hebrew University Medical Center ( Site 0021)
city: Ramat-Gan
country: Israel
facility: Sheba Medical Center - Cancer Center ( Site 0002)
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Fondazione Pascale ( Site 3903)
city: Padova
country: Italy
facility: IRCCS Istituto Oncologico Veneto ( Site 3905)
city: Siena
country: Italy
facility: Policlinico Le Scotte - A.O. Senese ( Site 3907)
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East ( Site 0014)
state: Chiba
city: Akashi
country: Japan
facility: Hyogo Cancer Center ( Site 0015)
state: Hyogo
city: Seoul.
country: Korea, Republic of
facility: Asan Medical Center ( Site 0006)
state: Seoul
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital ( Site 0007)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System ( Site 0008)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center ( Site 0010)
city: Christchurch
country: New Zealand
facility: Canterbury District Health Board ( Site 0023)
state: Canterbury
city: Auckland
country: New Zealand
facility: Auckland City Hospital ( Site 0016)
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Oddzial Badan Wczesnych Faz ( Site 4801
state: Mazowieckie
city: Poznan
country: Poland
facility: Szpital Kliniczny im. Heliodora Swiecickiego Uniwers Medyczn ( Site 4803)
state: Wielkopolskie
city: Johannesburg
country: South Africa
facility: Sandton Oncology Medical Group PTY LTD ( Site 2701)
state: Gauteng
city: Kraaifontein
country: South Africa
facility: Cape Town Oncology Trials Pty Ltd ( Site 2704)
state: Western Cape
city: Rondebosch
country: South Africa
facility: Cancercare Rondebosch Oncology ( Site 2706)
state: Western Cape
city: Hospitalet de Llobregat
country: Spain
facility: Instituto Catalan de Oncologia ICO - Hospital Duran i Reynals ( Site 3403)
state: Barcelona
city: San Sebastian
country: Spain
facility: Onkologikoa - Instituto Oncologico de San Sebastian ( Site 3405)
state: Gipuzkoa
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia ( Site 3404)
state: Valenciana, Comunitat
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona ( Site 3401)
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen de la Macarena ( Site 3402)
city: Lund
country: Sweden
facility: Skanes Universitetssjukhus Lund. ( Site 4601)
state: Skane Lan
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Perets R, Bar J, Rasco DW, Ahn MJ, Yoh K, Kim DW, Nagrial A, Satouchi M, Lee DH, Spigel DR, Kotasek D, Gutierrez M, Niu J, Siddiqi S, Li X, Cyrus J, Chackerian A, Chain A, Altura RA, Cho BC. Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small-cell lung cancer. Ann Oncol. 2021 Mar;32(3):395-403. doi: 10.1016/j.annonc.2020.11.020. Epub 2020 Dec 2.
citation: Cho BC, Yoh K, Perets R, Nagrial A, Spigel DR, Gutierrez M, Kim DW, Kotasek D, Rasco D, Niu J, Satouchi M, Ahn MJ, Lee DH, Maurice-Dror C, Siddiqi S, Ren Y, Altura RA, Bar J. Anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody quavonlimab in combination with pembrolizumab: Safety and efficacy from a phase I study in previously treated extensive-stage small cell lung cancer. Lung Cancer. 2021 Sep;159:162-170. doi: 10.1016/j.lungcan.2021.07.009. Epub 2021 Jul 18.