Clinical trial NCT06172478: A Study of HER3-DXd in Subjects With Locally Advanced or Metastatic Solid Tumors
Official title: HERTHENA-PanTumor01 (U31402-277): A Phase 2, Multicenter, Multicohort, Open-Label, Proof of Concept Study of Patritumab Deruxtecan (HER3-DXd; U3-1402) in Subjects With Locally Advanced or Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Advanced Solid Tumor
Melanoma
Head and Neck Cancer
Gastric Cancer
Ovarian Carcinoma
Cervical Cancer
Endometrial Cancer
Bladder Cancer
Esophageal Cancer
Pancreatic Carcinoma
Prostate Cancer
Keywords: Advanced Solid Tumor
Melanoma
Head and Neck Cancer
Gastric Cancer
Ovarian carcinoma
Cervical cancer
Endometrial cancer
Bladder cancer
Esophageal carcinoma
Pancreatic carcinoma
Prostate cancer
Patritumab Deruxtecan
HER3-DXd
U3-1402
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2023-12-15
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a proof-of-concept study designed to investigate HER3-DXd monotherapy in locally advanced or metastatic solid tumors. The study is enrolling cohorts of participants with melanoma \[cutaneous/acral\], squamous cell carcinomas of the head and neck (SCCHN), and HER2-negative gastric cancerovarian carcinoma, cervical cancer, endometrial cancer, bladder cancer, esophageal carcinoma, pancreatic carcinoma, and prostate cancer.

Detailed description: This study is designed to assess the safety and efficacy of HER3-DXd monotherapy in subjects with refractory locally advanced or metastatic solid tumors who have been previously treated with ≥1 prior line of systemic anticancer therapy.

The primary objective of the study is to assess the efficacy of HER3-DXd monotherapy for each type of indicated locally advanced or metastatic tumor. Secondary objectives include the assessment of safety and tolerability, efficacy, and pharmacokinetics of HER3-DXd monotherapy for each type of indicated locally advanced or metastatic tumor. HER3 protein expression in tumor tissue and its relationship with HER3-DXd efficacy will also be evaluated.

Eligibility criteria: Inclusion Criteria

Participants must meet all of the following criteria to be eligible for enrollment into the study:

1. Sign and date the informed consent form prior to the start of any study-specific qualification procedures. A separate tissue screening consent will be obtained from all subjects to meet the baseline tumor tissue requirement.
2. Participants aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is \>18 years old).
3. Has locally advanced unresectable or metastatic disease (not curable by surgery or radiation) as follows:

   Cutaneous (acral and non-acral) melanoma
   1. Histologically or cytologically confirmed cutaneous (acral or non-acral) melanoma
   2. Disease progression while on or after having received treatment with ≥1 prior line of anti-programmed cell death protein (PD-1) or anti-programmed death-ligand 1 (PD-L1) based therapy (previous use of other immune checkpoint inhibitors \[ICIs\] \[ie, anti-CTLA4, anti- LAG-3\] is acceptable). Prior anti-PD-(L)1 therapy in the adjuvant setting is allowed if there is recurrence within 12 weeks of the last dose. If the participant had BRAFm melanoma, they must have had disease progression on BRAF/MEK inhibitor therapy as well.

      Squamous cell carcinomas of the head and neck
   3. Squamous cell carcinoma of the head and neck (with a primary location of oral cavity,oropharynx, larynx, hypopharynx) that is human papillomavirus (HPV) positive or negative (as determined by local standard). Excludes tumor location in the nasopharynx, nasal cavity, paranasal sinuses, and unknown primary locations.
   4. Disease progression after having received treatment with ≥1 and \<3 prior lines of systemic therapy in the unresectable recurrent or metastatic setting.

      Must have had disease progression on anti-PD-(L)1 (either as monotherapy or in combination with chemotherapy or other therapies). Must also have had disease progression on a platinum-based chemotherapy (PBC) regimen either in the recurrent or metastatic setting or in the locally advanced setting with curative intent.

      Gastric or GEJ adenocarcinoma
   5. Tumor tissue must be confirmed as negative for HER2 expression (immunohistochemistry \[IHC\] 0/1+ or IHC 2+/in situ hybridization negative) as classified by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines and determined prior to enrollment by assessment in a local laboratory that is Clinical Laboratory Improvement Amendments certified (US sites) or accredited based on specific country regulations.
   6. Disease progression after having received treatment with ≥2 prior lines of therapy that include PBC with or without anti-PD-1 therapy.

      Ovarian Carcinoma
   7. Pathologically documented high-grade serous epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.
   8. Documented disease progression ≥4 weeks after the last dose of PBC and \<6 months of last dose of PBC in the advanced or metastatic setting. Prior use of folate reductase alpha targeting antibody-drug conjugate (ADC) (ie, mirvetuximab soravtansine) is allowed.

      Cervical Cancer
   9. Pathologically or cytologically documented recurrent or persistent squamous, adenosquamous, or adenocarcinoma of the uterine cervix.
   10. Disease progression after having received ≥1 line of systemic therapy in the recurrent or metastatic setting. This may include prior anti-PD-(L)1 treatment and/or tissue factor directed ADC (tisotumab vedotin \[TV\]) per regional standard of care.

       Endometrial Cancer
   11. Pathologically or cytologically documented endometrial cancer (carcinoma of any histological sub-type or endometrial carcinosarcoma), irrespective of microsatellite instability (MSI) or mismatch repair (MMR) status.
   12. Documented disease progression after having received ≥1 prior line of therapy (maximum of 3) PBC containing systemic treatment and an anti-PD(L)-1 therapy-containing regimen (combined or sequential) in the advanced/metastatic setting.

       Bladder Cancer
   13. Pathologically or cytologically documented locally advanced/unresectable or metastatic urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra. Histological variants are allowed if urothelial histology is predominant. Small cell/neuroendocrine tumors are not allowed even if mixed histology.
   14. Relapsed or progressed after treatment with ≥1 prior line of therapy (maximum of 3) that contains anti-PD-(L)1 therapy in the perioperative or metastatic setting. At least 1 line of therapy must also contain one of the following treatment modalities: chemotherapy or enfortumab vedotin. Prior fibroblast growth factor receptor (FGFR)-inhibitor treatment for those who are eligible are allowed.

       * Required treatments can be given in combination or sequentially
       * Prior cisplatin-based therapy or PD-(L)1 inhibitor therapy given for the treatment of muscle invasive urothelial carcinoma is counted as 1 line of therapy
       * The same regimen administered twice in different disease settings will be counted as 1 line of prior therapy
       * A minimum of 20 subjects in the second-line setting who have previously received enfortumab vedotin and pembrolizumab in combination will be enrolled.

       Esophageal Carcinoma
   15. Pathologically or cytologically documented esophageal squamous cell carcinoma.
   16. Must have documented disease progression after having received 2 prior lines of therapy including previous PBC with or without an anti-PD-1 therapy-containing regimen (combined or sequential) in the advanced/metastatic setting.

       Pancreatic Carcinoma
   17. Pathologically or cytologically documented unresectable or metastatic pancreatic adenocarcinoma.
   18. Relapsed or disease progression after having received 1 prior line of systemic therapy in the locally advanced/metastatic setting.

       Prostate Cancer
   19. Pathologically or cytologically documented unresectable locally advanced or metastatic castration-resistant prostate cancer (CRPC).
   20. Adenocarcinoma of the prostate without neuroendocrine differentiation or small cell histology.
   21. Surgically or medically castrated, with testosterone levels of \<50 ng/dL.
   22. Documented objective progression as determined by radiographic progression for subjects with measurable disease after androgen deprivation.
   23. Relapsed or disease progression after having received treatment with ≥1 of the following novel hormonal agents: abiraterone, enzalutamide, apalutamide, or darolutamide.
   24. Relapsed or disease progression after having received ≥1 cytotoxic chemotherapy regimen that included a taxane.
4. Has ≥1 measurable lesion on CT or MRI as per RECIST v1.1 by investigator assessment. Prostate cancer participants with bone only disease may be eligible.
5. Provides a pretreatment tumor tissue sample of sufficient quantity, as defined in the Study Laboratory Manual. The following tissue samples can be provided as the pretreatment tumor tissue sample:

   1. Tissue collected from a biopsy (from ≥1 lesion not previously irradiated) performed since progression while on or after treatment with the most recent systemic cancer therapy regimen and prior to signing of the tissue ICF

      OR
   2. Pretreatment tumor biopsy from ≥1 lesion not previously irradiated and amenable to sampling after signing of the tissue ICF. The pretreatment tissue requirement may be waived after discussion and agreement with the Sponsor.
6. Has Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at screening.

Exclusion Criteria

Participants who meet any of the following criteria will be disqualified from entering the study:

1. Has HER2-positive gastric cancer as classified by ASCO-CAP guidelines and determined prior to enrollment by assessment in a local laboratory that is Clinical Laboratory Improvement Amendments certified (US sites) or accredited based on specific country regulations.
2. Has nasopharyngeal cancer.
3. Has mucosal or uveal melanoma.
4. Has a history of (non-infectious) interstitial lung disease (ILD), that required corticosteroids, has current ILD/pneumonitis, or suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
5. Has clinically severe respiratory compromise (based on the investigator's assessment) resulting from intercurrent pulmonary illnesses
6. Is receiving chronic systemic corticosteroids dosed at \>10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to Cycle 1 Day 1.

   Participants who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study.
7. Had prior treatment with an anti-HER3 antibody and/or antibody-drug conjugate (ADC) that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, trastuzumab deruxtecan).
8. Has history of other active malignancy within 3 years prior to Cycle 1 Day 1, except the following:

   1. Adequately treated nonmelanoma skin cancer
   2. Adequately treated intraepithelial carcinoma of the cervix
   3. Any other curatively treated in situ disease
9. Has any evidence of severe or uncontrolled diseases (eg, active bleeding diatheses, active serious infection) psychiatric illness/social situations, geographical factors, substance abuse, or other factors that, in the investigator's opinion, make it high risk for the subject to participate in the study or that would jeopardize compliance with the protocol
10. Has previously received irinotecan treatment in the advanced or metastatic disease setting.

Primary outcomes:
measure: Number of Participants With Objective Response Rate Assessed by Investigator Following HER3-DXd Monotherapy (All Cohorts Except Prostate Cancer Cohort)
timeFrame: Baseline up until documented progressive disease, death, lost to follow-up, or withdrawal by the participant, up to approximately 27 months
measure: Proportion of Participants Achieving a ≥50% Decrease in PSA (Prostate Cancer Cohort Only)
timeFrame: Baseline, each cycle before infusion (each cycle is 21 days), and end of treatment, up to approximately 27 months
Secondary outcomes:
measure: Overall Number of Participants With Treatment-emergent Adverse Events Following HER3-DXd Monotherapy (All Cohorts)
timeFrame: Baseline up to 27 months
measure: Duration of Response As Assessed by Investigator Following HER3-DXd Monotherapy (All Cohorts Except Prostate Cancer Cohort)
timeFrame: From the date of first documentation of confirmed response (CR or PR) to the first documentation of objective progression or to death due to any cause, whichever occurs first, up to approximately 27 months
measure: Clinical Benefit Rate As Assessed by Investigator Following HER3-DXd Monotherapy (All Cohorts Except Prostate Cancer Cohort)
timeFrame: Baseline up until documented progressive disease, death, lost to follow-up, or withdrawal by the participant, up to approximately 27 months
measure: Disease Control Rate As Assessed by Investigator Following HER3-DXd Monotherapy (All Cohorts Except Prostate Cancer Cohort)
timeFrame: Baseline up until documented progressive disease, death, lost to follow-up, or withdrawal by the participant, up to approximately 27 months
measure: Time to Response As Assessed by Investigator Following HER3-DXd Monotherapy (All Cohorts Except Prostate Cancer Cohort)
timeFrame: From the start date of study drug to the date of the first documentation of response (CR or PR) that is subsequently confirmed, up to approximately 27 months
measure: Progression-free Survival As Assessed by Investigator Following HER3-DXd Monotherapy (All Cohorts Except Prostate Cancer Cohort)
timeFrame: From the start date of study drug to the earlier date of the first objective documentation of radiographic disease progression as assessed by investigator per RECIST v1.1 or death due to any cause, whichever occurs first, up to approximately 27 months
measure: Overall Survival Following HER3-DXd Monotherapy (All Cohorts)
timeFrame: From the start date of study drug to the date of death due to any cause, whichever occurs first, up to approximately 27 months
measure: Pharmacokinetic Parameter Maximum Serum Concentration for HER3-DXd (All Cohorts)
timeFrame: Cycles 1-4, 6, 8: Day 1, predose and postdose; Cycles 1 and 3: Day 1, 2 hours and 4 hours postdose; Cycles 1 and 3: Day 8; Cycle 1: Day 15 (each cycle is 21 days)
measure: Pharmacokinetic Parameter Time to Maximum Serum Concentration for HER3-DXd (All Cohorts)
timeFrame: Cycles 1-4, 6, 8: Day 1, predose and postdose; Cycles 1 and 3: Day 1, 2 hours and 4 hours postdose; Cycles 1 and 3: Day 8; Cycle 1: Day 15 (each cycle is 21 days)
measure: Pharmacokinetic Parameter Trough Serum Concentration (Ctrough) for HER3-DXd (All Cohorts)
timeFrame: Cycles 1-4, 6, 8: Day 1, predose and postdose; Cycles 1 and 3: Day 1, 2 hours and 4 hours postdose; Cycles 1 and 3: Day 8; Cycle 1: Day 15 (each cycle is 21 days)
measure: Pharmacokinetic Parameter Area Under the Concentration Curve for HER3-DXd (All Cohorts)
timeFrame: Cycles 1-4, 6, 8: Day 1, predose and postdose; Cycles 1 and 3: Day 1, 2 hours and 4 hours postdose; Cycles 1 and 3: Day 8; Cycle 1: Day 15 (each cycle is 21 days)
measure: Radiographic Progression-free Survival (rPFS) As Assessed by Prostate Cancer Working Group 3 (PCWG3) Criteria by the Investigator or Death Due to Any Cause Following HER3-DXd Monotherapy (Prostate Cancer Cohort Only)
timeFrame: From the start date of study drug to the earlier date of the first objective documentation of radiographic disease progression as assessed per PCWG3 criteria by investigator or death due to any cause, whichever occurs first, up to approximately 27 months
measure: Proportion of Participants Achieving a ≥30% Decrease in PSA (Prostate Cancer Cohort Only)
timeFrame: Baseline, each cycle before infusion (each cycle is 21 days), and end of treatment, up to approximately 27 months
measure: Time to First Subsequent Anticancer Therapy (TFST) (Prostate Cancer Cohort Only)
timeFrame: From the start date of study drug to initiation of the first subsequent anticancer therapy or death, whichever occurs first, up to approximately 27 months
measure: Time to First Symptomatic Skeletal-Related Event (SSRE) (Prostate Cancer Cohort Only)
timeFrame: From start date of study drug to the first occurrence of any of the following: Use of EBRT, New symptomatic pathologic bone fracture, Spinal cord compression, A tumor-related orthopedic surgical intervention, up to approximately 27 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Saint Louis Park
country: United States
facility: Health Partners Frauenshuh Cancer Center
state: Minnesota
city: Saint Paul
country: United States
facility: Health Partners Cancer Center at Regions Hospital
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University, School of Medicine
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute IDS
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Hospital
state: New York
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
city: Chermside
country: Australia
facility: Icon Cancer Centre Chermside
city: Clayton
country: Australia
facility: Monash Medical Centre Clayton
city: Hobart
country: Australia
facility: Icon Cancer Centre Hobart
city: Hyde Park
country: Australia
facility: Icon Cancer Centre Townsville
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Edegem
country: Belgium
facility: UZA
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Jette
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Leuven
country: Belgium
facility: UZ Leuven
city: Vancouver
country: Canada
facility: BC Cancer - Vancouver
city: Bordeaux
country: France
facility: Chu Bordeaux
city: Dijon
country: France
facility: Centre Georges Franăois Leclerc
city: Lille
country: France
facility: Hopital Claude Huriez - Chu Lille
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Hăpital de La Timone
city: Nantes
country: France
facility: Chu Nantes - Hătel Dieu
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Hidaka
country: Japan
facility: Saitama Medical University International Medical Center
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
city: Matsuyama-shi
country: Japan
facility: NHO Shikoku Cancer Center
city: Nagaizumi-cho
country: Japan
facility: Shizuoka Cancer Center
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital
city: Osakasayama-shi
country: Japan
facility: Kindai University Hospital
city: Tokyo
country: Japan
facility: National Cancer Center Hospital
city: Tokyo
country: Japan
facility: Cancer Institute Hospital of JFCR
city: Yokohama
country: Japan
facility: Yokohama City University Medical Center
city: Seongnam
country: Korea, Republic of
facility: Cha Bundang Medical Center, Cha University
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Barcelona
country: Spain
facility: Hospital Universitari Vall D'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu I Sant Pau
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario Ramon Y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Málaga
country: Spain
facility: HOSPITAL REGIONAL UNIVERSITARIO de MALAGA AVDA.
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital
city: Coventry
country: United Kingdom
facility: University Hospital Coventry
city: London
country: United Kingdom
facility: Barts Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital Campus
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References: