Advanced Solid Tumors
Conditions
Keywords
B7-H3, SCLC (small cell lung cancer), NSCLC (non-small cell lung cancer), ESCC (esophageal squamous cell carcinoma), CRPC (castration-resistant prostate cancer), Melanoma, HCC (Hepatocellular Carcinoma), HNSCC (Head and neck squamous cell carcinomas), CC (Cervical Cancer), PROC (platinum-resistant ovarian cancer), PC (prostate cancer), CSPC (castration-sensitive prostate cancer)
Brief summary
This is a dose-escalation and dose-expansion Phase 1/2a trial to evaluate the safety and tolerability of DB-1311/BNT324 in subjects with advanced solid tumors.
Detailed description
This is a multicenter, open-label, multiple-dose, FIH Phase 1/2a study. Phase 1 adopts an accelerated titration at first dose level followed with classic 3+3 design to identify the MTD (maximum tolerated dose) and/or RP2D(Recommended Phase 2 Dose). Phase 2a is a dose expansion phase to confirm the safety, tolerability and explore efficacy in selected malignant solid tumors treated with DB-1311/BNT324 as monotherapy or in combination with novel hormone therapy (NHT) in prostate cancer (PC). And the drug-drug-interaction (DDI) sub-study to evaluate the effect of lopinavir/ritonavir and itraconazole on the PK of DB-1311 and its payload.
Interventions
DRUGDB-1311
Administered I.V.(intravenous infusion)
Lopinavir and Ritonavir Tablets
DRUGitraconazole
itraconazole
DRUGEnzalutamide
oral administration
DRUGAbiraterone
oral administration
Sponsors
BioNTech SE
DualityBio Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female adults (defined as ≥ 18 years of age or acceptable age according to local regulations at the time of voluntarily signing of informed consent). 2. Histologically or cytologically confirmed unresectable advanced/metastatic solid tumor that has relapsed or progressed on or after standard systemic treatments, or is intolerable with standard treatment; or for which no standard treatment is available. 3. At least one measurable lesion as assessed by the investigator according to response evaluation criteria in solid tumors (RECIST) version 1.1 criteria (measurable disease as defined by RANO 2.0 criteria for GBM subjects). Castrate-resistant prostate cancer (CRPC) subjects with bone only disease may be eligible on a case-by- case basis after discussion with the Medical Monitor. 4. Has a life expectancy of ≥ 3 months. 5. Has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1. 6. Has LVEF ≥ 50% by either echocardiography (ECHO) or multiple-gated acquisition (MUGA) within 28 days before enrollment. 7. Has adequate organ function within 7 days prior to Day 1 of Cycle 1 8. Has adequate treatment washout period prior to Day 1 of Cycle 1 9. Is willing to provide pre-existing resected tumor samples or undergo fresh tumor biopsy for the measurement of B7-H3 level and other biomarkers if no contraindication. Note: there is no minimum B7-H3 expression level mandatory for entry into the study. 10. Is capable of comprehending study procedures and risks outlined in the informed consent and able to provide written consent and agree to comply with the requirements of the study and the schedule of assessments. 11. Male and female subjects of reproductive/childbearing potential must agree to use adequate contraceptive methods (e.g., double barrier or intrauterine contraceptive) during the study and for at least 4 months and 7 months after the last dose of study drug, respectively. 12. Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and at least 4 months after the final study drug administration. 13. Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration. 14. SCLC subjects (Phase 2a Cohort 1 ONLY): * Pathologically documented locally advanced, or metastatic SCLC not amenable to curative surgery or radiation. * Prior therapy with at least one platinum-based line as systemic therapy for extensive stage disease with at least two cycles of therapy (except in the case of early objective PD). * Prior treatment regimens with irinotecan, topotecan or any other TOP I inhibitor including investigational TOP I inhibitors are not allowed. 15. NSCLC subjects (Phase 2a Cohort 2 ONLY): * Pathologically documented locally advanced, or metastatic NSCLC and is not amenable to curative surgery or radiation. * Has received prior treatment with platinum-based chemotherapy regimen and/or anti-PD-1/PD-L1 antibody-based regimen in the advanced/unresectable, or metastatic setting unless unable or unwilling. Subjects with NSCLC known to harbor a genomic alteration(s) other than EGFR mutation(s) (e.g., ALK rearrangement, ROS1 rearrangement, KRAS G12C mutation, BRAF V600E mutation, NTRK1/2/3 Gene fusion, MET Exon 14 skipping, RET rearrangement etc.) for which treatment is available must have also received prior treatment with at least 1 genotype-directed therapy. 16. ESCC subjects (Phase 2a Cohort 3 ONLY): * Pathologically documented locally advanced, or metastatic ESCC and is not amenable to curative surgery or radiation. * Having received at least one prior therapy for unresectable disease. Patients with recurrence within 6 months of completion of neoadjuvant or adjuvant therapy will be considered as having received one prior therapy for unresectable disease. 17. CRPC subjects (Phase 2a Cohort 4 ONLY): • Pathologically documented metastatic adenocarcinoma of the prostate cancer. * Progressive metastatic CRPC as defined: 1) castrate levels of serum testosterone \< 50 ng/dL AND 2) progressive disease as defined by PCWG3 criteria. * Having received prior docetaxel (before or after an AR-targeted therapy). Docetaxel rechallenge was allowed. * Having received prior novel hormone therapy. 18. Melanoma subjects (Phase 2a Cohort 5 ONLY) • Histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic melanoma not amenable to local therapy, must have had either: \> Previously treated with a PD-1 or PD-L1 inhibitor. \> If subjects with BRAF gene mutant melanoma, must have had a prior treatment regimen that included vemurafenib, dabrafenib, or another BRAF gene and/or mitogen-activated protein kinase (MEK) protein inhibitor. 19. HCC subjects (Phase 2a Cohort 6 ONLY) * Histological/cytological confirmed diagnosis of HCC or clinically confirmed diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria (fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC are not eligible), and: * Has received 1 or 2 prior systemic therapy regimens for recurrent or metastatic disease; * Has experienced disease progression during or after treatment with an anti-PD-1/L1 agent administered either as monotherapy or in combination. Note: Subjects basically should receive prior standard therapy. • However, if the investigator judges the therapy is not appropriate for the subject, the prior standard therapy is not necessarily mandated for the eligibility. • Has a Child-Pugh class A liver score within 7 days of first dose of study drug. 20. Cervical cancer subjects (Phase 2a Cohort 7 ONLY) • Has recurrent or metastatic cervical cancer with squamous cell, adenocarcinoma, or adenosquamous histology, and: • Has experienced disease progression during or after treatment with a standard of care systemic chemotherapy doublet, or platinum-based therapy (if eligible), defined as either: d. paclitaxel + cisplatin + bevacizumab + anti-PD-(L)1 agent, or e. paclitaxel + carboplatin + bevacizumab + anti-PD-(L)1 agent, or f. paclitaxel + topotecan + bevacizumab + anti-PD-(L)1 agent Note: In cases where bevacizumab and/or anti-PD-(L)1 agent is not a standard of care therapy or the subject was ineligible for such treatment according to local standards, prior treatment with bevacizumab and/or anti-PD-(L)1 agent is not required. • Has received 1 or 2 prior systemic therapy regimens for recurrent or metastatic cervical cancer. Chemotherapy administered in the adjuvant or neoadjuvant setting, or in combination with radiation therapy, should not be counted as a systemic therapy regimen. Single agent therapy with an anti-PD(L)1 agent for recurrent or metastatic cervical cancer should be counted. 21. Subjects with other solid tumors (Phase 2a Cohort 8 ONLY) • Histologically or cytologically confirmed solid tumors. • Progressed or relapsed after at least one prior standard therapeutic regimen (Patients who have not received all approved or standard treatments for their cancer must be informed that these alternatives to receiving DB-1311/BNT324 are available prior to consenting to participate in this trial). 22. HNSCC subjects (Phase 2a Cohort 9 and Cohort 13) • Histologically or cytologically confirmed refractory/metastatic (R/M) HNSCC (not including NPC) that is considered incurable by local therapies. • Progressed on or after prior standard therapeutic regimen. 23. Subjects with rare tumors (Phase 2a Cohort 10 ONLY) Histologically or cytologically confirmed rare tumor types. Progressed or relapsed after at least one prior standard therapeutic regimen (Patients who have not received all approved or standard treatments for their cancer must be informed that these alternatives to receiving DB-1311/BNT324 are available prior to consenting to participate in this trial). 24. Post lutetium-177 CRPC subjects (Phase 2a Cohort 11 ONLY): Pathologically documented metastatic adenocarcinoma of the prostate cancer. Progressive metastatic CRPC as defined: 1) castrate levels of serum testosterone \< 50 ng/dL AND 2) progressive disease as defined by PCWG3 criteria. 25. Taxane-naive CRPC subjects (Phase 2a Cohort 12, 16, 17 ONLY) * Pathologically documented metastatic adenocarcinoma of the prostate cancer. Progressive metastatic CRPC as defined: 1) castrate levels of serum testosterone \< 50 ng/dL AND 2) progressive disease as defined by PCWG3 criteria. 26, PROC subjects (Phase 2a Cohort 14 ONLY) * Subjects must have a confirmed diagnosis of OC, primary peritoneal cancer, or fallopian tube cancer, all of which with high-grade serous or endometrioid histology.. * Subjects must have platinum-resistant disease: * Received at least 1 but ≤ 3 lines of prior systemic anticancer therapy and have radiographic progressed on or after their most recent line of therapy. 27\. CSPC with suboptimal PSA response (Phase 2a Cohort 18 ONLY) * Pathologically documented adenocarcinoma of the prostate cancer. * Having advanced/unresectable, or metastatic disease and confirmed by imaging (e.g., CT and/or bone scan). * Having received ADT and enzalutamide or abiraterone for ≥4 months, with suboptimal PSA response. 28\. Additional inclusion criteria for DDI cohort: has a study treatment expectancy of \>= 2.5 months. Able to withhold CYP3A/P-gp/OATP1B inhibitors or substrates or CYP3A inducers as concomitant treatments for certain period.
Exclusion criteria
Unless otherwise specified, the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Percentage of Participants with Dose-Limiting Toxicities (DLTs) as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Percentage of participants in Part 1 with DLTs | up to 21 days after Cycle 1 Day 1 | Percentage of participants in Part 1 with DLTs |
| Phase 1& Phase 2a: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs) as assessed by CTCAE v5.0. | Up to follow-up period, approximately 1 year post-treatment | Percentage of participants with TEAEs graded according to National Cancer Institute (NCI) CTCAE v5.0 |
| Phase 1& Phase 2a: Percentage of Participants with Serious Adverse Events (SAEs) as assessed by CTCAE v5.0. | Up to follow-up period, approximately 1 year post-treatment | Percentage of Participants with SAEs graded according to NCI CTCAE v5.0 |
| Phase 1 & Phase 2a: vital sign measurements | Up to follow-up period, approximately 1 year post-treatment | — |
| Phase 1& Phase 2a: clinical safety laboratory parameters | Up to follow-up period, approximately 1 year post-treatment | — |
| Phase 1& Phase 2a: Electrocardiogram (ECG) parameters | Up to follow-up period, approximately 1 year post-treatment | — |
| Phase 1& Phase 2a: Eastern Cooperative Oncology Group (ECOG) performance status (PS) | Up to follow-up period, approximately 1 year post-treatment | — |
| Phase 1& Phase 2a: left ventricular ejection fraction (LEVF) | Up to follow-up period, approximately 1 year post-treatment | — |
| Phase 1: Maximum Tolerated Dose (MTD) of DB-1311/BNT324 | Up to the completion of Part 1 (assessed up to 12 months) | MTD on the data collected during Part 1 |
| Phase 1: Recommended Phase 2 Dose (RP2D) of DB-1311/BNT324 | Up to the completion of Part 1 (assessed up to 12 months) | RP2D of DB-1311/BNT324 based on the data collected during Part 1 |
| Phase 2a: Objective Response Rate (ORR) as determined by investigator | Up to follow-up period, approximately 1 year post-treatment | Objective Response Rate (ORR) as determined by investigator per RECIST 1.1 in non-PC/non-GBM participants per RECIST v1.1 for soft tissue and Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases in PC participants, and ORR per neuro-oncology 2.0 (RANO 2.0) criteria in GBM participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 & Phase 2a: Pharmacokinetic-Tmax | within 8 cycles (each cycle is 21 days) | Time to Cmax of DB-1311/BNT324 ADC, total anti-B7-H3 antibody, and unconjugated P1021 |
| Phase 1 & Phase 2a: Pharmacokinetic-Cthrough | within 8 cycles (each cycle is 21 days) | Trough concentration |
| Phase 1: Objective response rate (ORR) | Up to follow-up period, approximately 1 year post-treatment | ORR will be determined by investigator per RECIST v1.1 in non-CRPC participants, and per RECIST v1.1 for soft tissue and PCWG3 criteria for bone metastases in CRPC participants |
| Phase 1 & 2a: ADA incidence | Up to follow-up period, approximately 1 year post-treatment | Percentage of participants having treatment-emergent ADA |
| Phase 1 & 2a: Anti-drug antibody (ADA) prevalence | Up to follow-up period, approximately 1 year post-treatment | Percentage of participants who are ADA positive at any point |
| Phase 1 & Phase 2a: duration of response (DoR) | Up to follow-up period, approximately 1 year post-treatment | DoR will be determined by investigator per RECIST v1.1 in non-PC/non-GBM participants, per RECIST v1.1 for soft tissue and PCWG3 criteria for bone metastases in PC participants, and per RANO 2.0 criteria in GBM participants |
| Phase 1 & Phase 2a: disease-control rate (DCR) | Up to follow-up period, approximately 1 year post-treatment | DCR will be determined by investigator per RECIST v1.1 in non-PC/non-GBM participants, per RECIST v1.1 for soft tissue and PCWG3 criteria for bone metastases in PC participants, and per RANO 2.0 criteria in GBM participants |
| Phase 1 & Phase 2a: Time to Response (TTR) | Up to follow-up period, approximately 1 year post-treatment | TTR will be determined by investigator per RECIST v1.1 in non-PC/non-GBM participants, per RECIST v1.1 for soft tissue and PCWG3 criteria for bone metastases in PC participants, and per RANO 2.0 criteria in GBM participants |
| Phase 1 & Phase 2a: Progression Free Survival (PFS) | Up to follow-up period, approximately 1 year post-treatment | PFS will be determined by investigator per RECIST v1.1 in non-PC/non-GBM participants, and per RANO 2.0 criteria in GBM participants |
| Phase 1 & Phase 2a: Radiographic Progression Free Survival (rPFS) | Up to follow-up period, approximately 1 year post-treatment | rPFS will be determined by investigator per RECIST v1.1 for soft tissue and PCWG3 criteria for bone metastases in PC participants |
| Phase 1 & Phase 2a: Overall Survival (OS) | From date of first dose until the date of death or lost to follow up, approximately 1 year post-treatment | OS is defined as the time from date of first dose to the date of death. |
| Phase 2a: Prostate-specific antigen (PSA) | From date of first dose until the date of first PSA progression, approximately 1 year post-treatment | Time to PSA progression, PSA50 response rate and PSA90 response rate, duration of PSA response in PC participants and the rate of PSA conversion to \<0.2 in CSPC. |
| Phase 2a: CA-125 response rate | Up to follow-up period, approximately 1 year post-treatment | CA-125 response assessed per GCIG criteria for ovarian cancer subjects |
| Phase 1 & Phase 2a: Pharmacokinetic-AUC | within 8 cycles (each cycle is 21 days) | Area under the concentration-time curve from time 0 to infinity of DB-1311/BNT324 ADC, total anti-B7-H3 antibody, and unconjugated P1021 |
| Phase 1 & Phase 2a: Pharmacokinetic-Cmax | within 8 cycles (each cycle is 21 days) | Maximum observed plasma concentration (Cmax) of DB-1311/BNT324 ADC, total anti-B7-H3 antibody, and unconjugated P1021 |
Countries
Australia, China, Taiwan, United States
Contacts
Primary ContactLing Li
Backup ContactTiana Zhao
Outcome results
None listed