Clinical trial NCT05579366: Rinatabart Sesutecan (Rina-S, PRO1184, GEN1184) for Advanced Solid Tumors (GCT1184-01/ PRO1184-001)
Official title: Phase 1/2 Study of Rina-S in Patients With Locally Advanced and/or Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: High Grade Epithelial Ovarian Cancer
High Grade Serous Ovarian Cancer
Primary Peritoneal Carcinoma
Fallopian Tube Cancer
Endometrial Cancer
Non-small Cell Lung Cancer
Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small Cell Lung Cancer (NSCLC)
Mesothelioma
Breast Adenocarcinoma
Triple Negative Breast Cancer
Hormone Receptor-positive/Her2 Negative Breast Cancer
Platinum-resistant Ovarian Cancer (PROC)
Platinum Sensitive Ovarian Cancer (PSOC)
Primary Refractory Ovarian Cancer
Uterine Cancer
Keywords: antibody-drug conjugate
folate receptor alpha
folate receptor
solid tumor
ovarian cancer
primary peritoneal carcinoma
fallopian tube cancer
endometrial cancer
non-small cell lung cancer
mesothelioma
breast cancer
triple negative breast cancer
hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer
topoisomerase I inhibitor
PROC
epidermal growth factor receptor (EGFR)-mutated NSCLC
Lead sponsor: Genmab
Sponsor class: INDUSTRY
First posted: 2022-10-13
Enrollment: 529
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study will test the safety, including side effects, and determine the characteristics of a drug called Rina-S in participants with solid tumors.

Participants will have solid tumor cancer that has spread through the body (metastatic) or cannot be removed with surgery (unresectable).

Detailed description: This is a Phase 1/2 study of Rina-S; also known as GEN1184, formerly known as PRO1184, a folate receptor alpha (FRα) targeted antibody-drug conjugate, to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of Rina-S in participants with selected locally advanced and/or metastatic solid tumors, including epithelial ovarian cancer, endometrial cancer, breast cancer, non-small cell lung cancer, and mesothelioma.

The study consists of multiple parts:

Part A: monotherapy cohorts

Part B: tumor-specific monotherapy dose-expansion cohorts

Part C: platinum-resistant ovarian cancer (PROC) cohort

Part D: combination therapy cohorts

Part F: a monotherapy endometrial cancer cohort

Participants will continue to receive study treatment until the first instance of disease progression, unacceptable toxicity, investigator decision, consent withdrawal, study termination by the Sponsor, pregnancy, or death.

Eligibility criteria: Inclusion Criteria:

Part A and B:

* Histologically or cytologically confirmed metastatic or unresectable solid malignancy including ovarian cancer (must have epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer), endometrial cancer, non-small cell lung cancer (Part A), EGFR-mutated NSCLC (Part B), breast cancer (hormone receptor positive, HER2-negative and triple-negative) (Part A), mesothelioma.
* Previously received therapies known to confer clinical benefit.
* Measurable disease per RECIST v1.1 for all tumor types other than pleural mesothelioma which will use mRECIST v1.1 at baseline.

Part C:

Participants must have histologically or cytologically confirmed metastatic or unresectable epithelial ovarian cancer as specified below.

* High grade serous ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (excluding endometrioid, clear cell carcinomas, mucinous, low grade, and those with a sarcomatous or neuroendocrine element)
* Participants must have received 1 to 3 prior lines of therapy. Participants who had 1 to 4 prior lines of therapy are allowed if mirvetuximab soravtansine (MIRV) was the last line of therapy. Participants must have progressed radiographically on or after their most recent line of therapy.
* Participants must have platinum-resistant ovarian cancer.
* Participants must have received prior bevacizumab.
* Participants with known or suspected deleterious germline or somatic BRCA mutations (as determined by Food and Drug Administration \[FDA\]-approved test in a Clinical Laboratory Improvement Amendments \[CLIA\]-certified laboratory) and who achieved a complete or partial response to platinum-based chemotherapy must have been treated with a poly ADP-ribose polymerase (PARP) inhibitor as maintenance treatment.
* Participants must have known FRα status based on an FDA approved test. Those who are FRα positive must have previously received MIRV, unless the participant has a documented medical exception.
* Participants who are FRα negative, in accordance with the FDA approved test (Ventana folate receptor \[FOLR1\] RxDx Assay), and were treated with MIRV, are excluded.
* Measurable disease per the RECIST v1.1 at baseline.

Part D:

Cohort D1 (Rina-S+carboplatin):

* Participants must have platinum-sensitive ovarian cancer.
* Participants must have received 1 to 3 prior lines of therapy.

Cohort D2 (Rina-S+bevacizumab):

* Participants must have primary platinum-refractory, platinum-resistant, or platinum-sensitive ovarian cancer.
* Participants with primary platinum-refractory ovarian cancer must have received ≤2 prior lines of therapy. Primary platinum-refractory ovarian cancer is defined as a lack of response or by progression within 91 days after completing front-line platinum containing therapy.
* Participants must have received 1 to 3 prior lines of therapy for platinum-resistant ovarian cancer (PROC), and up to 4 prior lines of therapy for platinum-sensitive ovarian cancer (PSOC). Prior treatments may have included bevacizumab, PARP inhibitor, and MIRV.

  * Participants with PSOC must have disease progression on or after maintenance treatment, or at least 6 months (\>183 days) or more from the last dose of platinum-based therapy.

Cohort D3 (Rina-S+pembrolizumab):

* Endometrial cancer (any subtype excluding sarcoma).
* Participants must have received prior platinum-based chemotherapy for recurrent or advanced disease.

Part F:

* Participants must have histologically or cytologically confirmed endometrial cancer as specified below.
* Advanced, recurrent, metastatic, or primary unresectable endometrial cancer (any subtype excluding neuroendocrine tumors, carcinosarcoma, or endometrial sarcoma)
* Participants must have received 1 to 3 prior lines of therapy in advanced, recurrent, or metastatic setting, and must have progressed radiographically on or after their most recent line of therapy:
* Participants must have received prior platinum-based chemotherapy and a programmed death-ligand 1 (PD-\[L\])1 inhibitor.
* Participants who progress \>12 months after completion of prior adjuvant or neoadjuvant platinum-based chemotherapy must receive 1 additional cytotoxic systemic treatment prior to enrollment in this study.
* Hormonal therapy alone (i.e., without chemotherapy) will not be counted as a separate line of therapy.
* Measurable disease per the RECIST Version 1.1 at baseline.

Exclusion Criteria:

* History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids within the past 2 years, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
* Use of a strong cytochrome P450 3A (CYP3A) inhibitor within 14 days (dose escalation only).
* Prior therapy with a topoisomerase 1 inhibitor-based antibody drug conjugate.

Note: Other protocol-defined inclusion/exclusion may apply.

Primary outcomes:
measure: Parts A, B, and D - Incidence of Treatment-Emergent Adverse Events (TEAEs) [Safety and Tolerability]
timeFrame: Through end of treatment, up to approximately 1 year.
measure: Parts A, and D - Dose Limiting Toxicity (DLT)
timeFrame: At the end of Cycle 1 (each cycle is 21 days)
measure: Parts C and F- Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
timeFrame: Through end of treatment, up to approximately 1 year.
Secondary outcomes:
measure: Parts A, B, and D - Best Overall Response (BOR)
timeFrame: Up to approximately 1 year.
measure: Parts A, B, and D - ORR
timeFrame: Up to approximately 1 year.
measure: Parts A, B, and D - Disease Control Rate (DCR)
timeFrame: Up to approximately 1 year.
measure: Parts A, B, C, D and F - Progression-Free Survival (PFS)
timeFrame: Through end of treatment, up to approximately 1 year.
measure: Parts C and F - Overall survival (OS)
timeFrame: Up to approximately 2 years.
measure: Parts A, B, C, D and F - Duration of Objective Response (DOR)
timeFrame: From date of enrollment until the date of first documented disease progression or date of study withdrawal, whichever came first, assessed up to 12 months.
measure: Parts A, B, and D - Peak Plasma Concentration (Cmax) for Rina-S
timeFrame: Through end of treatment, up to approximately 1 year.
measure: Parts A, B, and D - Area Under the Plasma Concentration Versus Time Curve (AUC) for Rina-S
timeFrame: Through end of treatment, up to approximately 1 year.
measure: Parts A, B, and D -Time to Reach Cmax (Tmax) for Rina-S
timeFrame: Through end of treatment, up to approximately 1 year
measure: Parts A, B, and D - Trough Concentrations (Ctrough) for Rina-S
timeFrame: Through end of treatment, up to approximately 1 year
measure: Parts A, B, and D - Apparent Terminal Half-life (t1/2) for Rina-S
timeFrame: Through end of treatment, up to approximately 1 year
measure: Parts C and D - CA-125 Response Determined Using the Gynecologic Cancer Intergroup (GCIG) Criteria
timeFrame: Through end of treatment, up to approximately 1 year
measure: Parts C and F - Number of Participants with Type, Incidence, Severity, Seriousness as per Common Terminology Criteria for Adverse Events (CTCAE) v5.0, and Relatedness of Adverse Events (AEs)
timeFrame: Through end of treatment, up to approximately 1 year
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: USOR HonorHealth
state: Arizona
city: Tucson
country: United States
facility: USOR Arizona Oncology Associates
state: Arizona
city: Los Angeles
country: United States
facility: University of California Los Angeles Medical Center
state: California
city: San Diego
country: United States
facility: University of California, San Diego; Moores Cancer Center
state: California
city: Santa Barbara
country: United States
facility: USOR Sansum Clinic
state: California
city: Santa Rosa
country: United States
facility: Providence Medical Foundation
state: California
city: Fort Myers
country: United States
facility: USOR Florida Cancer Specialists South
state: Florida
city: Saint Petersburg
country: United States
facility: USOR Florida Cancer Specialists North
state: Florida
city: West Palm Beach
country: United States
facility: USOR Florida Cancer Specialists East
state: Florida
city: Westwood
country: United States
facility: University of Kansas Medical Center (KUMC)
state: Kansas
city: Rockville
country: United States
facility: USOR Maryland Oncology Hematology
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Grand Rapids
country: United States
facility: START Midwest
state: Michigan
city: Maplewood
country: United States
facility: USOR Minnesota Oncology Hematology
state: Minnesota
city: Oklahoma City
country: United States
facility: University of Oklahoma - Health Sciences Center
state: Oklahoma
city: Eugene
country: United States
facility: USOR Oncology Associates of Oregon, P.C.
state: Oregon
city: Portland
country: United States
facility: Compass Oncology - Rose Quarter
state: Oregon
city: Doylestown
country: United States
facility: USOR Alliance Cancer Specialist
state: Pennsylvania
city: Providence
country: United States
facility: Women and Infants Hospital of Rhode Island
state: Rhode Island
city: Nashville
country: United States
facility: Sarah Cannon Research Institute at Tennessee Oncology
state: Tennessee
city: Abilene
country: United States
facility: USOR Texas Oncology
state: Texas
city: Austin
country: United States
facility: Texas Oncology - Central / South Texas
state: Texas
city: Dallas
country: United States
facility: Mary Crowley Cancer Research
state: Texas
city: Fort Worth
country: United States
facility: USOR Texas Oncology
state: Texas
city: Tyler
country: United States
facility: Texas Oncology - Northeast TX
state: Texas
city: Woodland
country: United States
facility: USOR Texas Oncology Gulf Coast
state: Texas
city: West Valley City
country: United States
facility: START Mountain Region
state: Utah
city: Fairfax
country: United States
facility: USOR Virginia Cancer Specialists
state: Virginia
city: Norfolk
country: United States
facility: USOR Virginia Oncology Associates
state: Virginia
city: Beijing
country: China
facility: Cancer hospital, Chinese Academy of Medical Sciences
state: Beijing
city: Changsha
country: China
facility: Hunan Cancer Hospital - Phase 1
state: Hunan
city: Changsha
country: China
facility: Hunan Cancer Hospital - Thoracic Medicine Dept II
state: Hunan
city: Chang chun
country: China
facility: Jilin Cancer Hospital
state: Jilin
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center - Gynecologic Oncology
state: Shanghai
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center- Phase 1
state: Shanghai
Study officials:
affiliation: Genmab
name: Study Official
role: STUDY_DIRECTOR
References: