A Study of HER3-DXd in Subjects With Locally Advanced or Metastatic Solid Tumors

Prostate Cancer Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06172478
• Other study ID #: U31402-277
• Secondary ID: 2023-507641-29-0
• Status: Recruiting
• Phase: Phase 2
• Start date: February 26, 2024
• Est. completion date: April 30, 2026

Study information

• Verified date: May 2024
• Source: Daiichi Sankyo
• Contact: Daiichi Sankyo Contact for Clinical Trial Information
• Phone: 9089926400
• Email: CTRinfo[@]dsi.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: April 30, 2026
• Est. primary completion date: June 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Bladder Cancer
• Carcinoma
• Carcinoma, Ovarian Epithelial
• Cervical Cancer
• Endometrial Cancer
• Endometrial Neoplasms
• Esophageal Cancer
• Gastric Cancer
• Head and Neck Cancer
• Head and Neck Neoplasms
• Melanoma
• Ovarian Carcinoma
• Ovarian Neoplasms
• Pancreatic Carcinoma
• Pancreatic Neoplasms
• Prostate Cancer
• Prostatic Neoplasms
• Stomach Neoplasms
• Urinary Bladder Neoplasms
• Uterine Cervical Neoplasms

Intervention

Drug:
• HER3-DXd
Intravenous infusion 5.6 mg/kg administered Q3W on Day 1 of each 21-day cycle

Locations

Country	Name	City	State
Japan	National Cancer Center Hospital East	Kashiwa-shi
Japan	NHO Shikoku Cancer Center	Matsuyama-shi
Japan	Kindai University Hospital	Osakasayama-shi
Japan	Shizuoka Cancer Center	Sunto-gun
Japan	Cancer Institute Hospital of JFCR	Tokyo
Taiwan	Taipei Veterans General Hospital	Taipei
United States	City of Hope	Duarte	California
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	SCRI Oncology Partners	Nashville	Tennessee
United States	Washington University, School of Medicine	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Daiichi Sankyo	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Japan,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Objective Response Rate Assessed by Investigator Following HER3-DXd Monotherapy (All Cohorts Except Prostate Cancer Cohort)	Confirmed objective response rate (ORR) is defined as the sum of the complete response (CR) rate and partial response (PR) rate based on investigator by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1.	Baseline up until documented progressive disease, death, lost to follow-up, or withdrawal by the participant, up to approximately 27 months
Primary	Proportion of Participants Achieving a =50% Decrease in PSA (Prostate Cancer Cohort Only)		Baseline, each cycle before infusion (each cycle is 21 days), and end of treatment, up to approximately 27 months
Secondary	Overall Number of Participants With Treatment-emergent Adverse Events Following HER3-DXd Monotherapy (All Cohorts)	Adverse events (AEs) will be coded using MedDRA and AEs and will be graded by using NCI-CTCAE v5.0.	Baseline up to 27 months
Secondary	Duration of Response As Assessed by Investigator Following HER3-DXd Monotherapy (All Cohorts Except Prostate Cancer Cohort)	Duration of response (DoR) is defined as the time from the date of the first documentation of objective response (complete response [CR] or partial response [PR]) to the date of the first documentation of progressive disease (PD) or death. The DoR will be calculated for responding participants (PR or CR) only.	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
Secondary	Clinical Benefit Rate As Assessed by Investigator Following HER3-DXd Monotherapy (All Cohorts Except Prostate Cancer Cohort)	Clinical benefit rate (CBR) is the proportion of participants with a best overall response of confirmed CR, confirmed PR, or SD lasting =183 days.	Baseline up until documented progressive disease, death, lost to follow-up, or withdrawal by the participant, up to approximately 27 months
Secondary	Disease Control Rate As Assessed by Investigator Following HER3-DXd Monotherapy (All Cohorts Except Prostate Cancer Cohort)	Disease control rate is defined as the proportion of participants who have achieved a best overall response of confirmed CR, confirmed PR, or SD (or non-CR/non-PD) by investigator assessment per RECIST v1.1.	Baseline up until documented progressive disease, death, lost to follow-up, or withdrawal by the participant, up to approximately 27 months
Secondary	Time to Response As Assessed by Investigator Following HER3-DXd Monotherapy (All Cohorts Except Prostate Cancer Cohort)	Time to response (TTR) will be calculated for confirmed responders only.	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
Secondary	Progression-free Survival As Assessed by Investigator Following HER3-DXd Monotherapy (All Cohorts Except Prostate Cancer Cohort)		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
Secondary	Overall Survival Following HER3-DXd Monotherapy (All Cohorts)		From the start date of study drug to the date of death due to any cause, whichever occurs first, up to approximately 27 months
Secondary	Pharmacokinetic Parameter Maximum Serum Concentration for HER3-DXd (All Cohorts)	Maximum serum concentration (Cmax) will be assessed using non-compartmental methods.	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)
Secondary	Pharmacokinetic Parameter Time to Maximum Serum Concentration for HER3-DXd (All Cohorts)	Time to maximum serum concentration (Tmax) will be assessed using non-compartmental methods.	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)
Secondary	Pharmacokinetic Parameter Trough Serum Concentration (Ctrough) for HER3-DXd (All Cohorts)	Trough serum concentration (Ctrough) will be assessed using non-compartmental methods.	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)
Secondary	Pharmacokinetic Parameter Area Under the Concentration Curve for HER3-DXd (All Cohorts)	Area under the concentration-time curve up to the last quantifiable time (AUClast) and Area under the concentration-time curve during dosing interval (AUCtau) will be assessed using non-compartmental methods.	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)
Secondary	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)		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
Secondary	Proportion of Participants Achieving a =30% Decrease in PSA (Prostate Cancer Cohort Only)		Baseline, each cycle before infusion (each cycle is 21 days), and end of treatment, up to approximately 27 months
Secondary	Time to First Subsequent Anticancer Therapy (TFST) (Prostate Cancer Cohort Only)		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
Secondary	Time to First Symptomatic Skeletal-Related Event (SSRE) (Prostate Cancer Cohort Only)		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