Key Inclusion Criteria (applicable to all participants and all parts unless otherwise
specified):
- - Aged ≥18 years at the time of giving informed consent.
- - Have histologic or cytologic documented advanced disease, either at relapse or upon
diagnosis of metastatic disease.
This requirement may be considered met when
advanced disease derives from unequivocal progression of a previously biopsied site
of disease (e.g., progression of residual tumor after concomitant chemo-radiation
for Stage III NSCLC).
- - Have measurable disease defined by RECIST 1.1.
- - All participants must provide a tumor tissue sample (Formalin-fixed
paraffin-embedded [FFPE] slides) from archival tissue.
The archival tissue can be an
FFPE block or freshly cut slides derived from the advanced setting or a new/fresh
tumor biopsy.
- - Have ECOG performance status of 0 or 1.
- - Have adequate organ and bone marrow function within 7 days before
randomization/enrollment.
- - Cohort 1A:
- Have histologically or cytologically confirmed diagnosis of unresectable or
metastatic cutaneous melanoma not amenable to local therapy.
- - Participants must have previously received a PD-1 or PD-L1 inhibitor, and, for
participants with human gene that encodes a protein called B-Raf (BRAF) gene
mutant melanoma, a prior treatment regimen that included vemurafenib,
dabrafenib, or another BRAF gene inhibitor with or without mitogen-activated
protein kinase protein inhibitor, if available and clinically indicated per
local standard of care (SoC) and have experienced progression during or after
the previous treatment or discontinued from prior therapy due to intolerance.
- - Cohort 1B and 1C: Have advanced (i.e., metastatic or locally recurrent where local
therapy with curative intent is not possible) non-squamous or squamous NSCLC.
- - Cohort 1B:
- Have no actionable genomic alterations, such as EGFR mutations, anaplastic
lymphoma kinase rearrangements, or other genomic alterations for which targeted
molecular therapies are available.
For enrolled participants with predominantly
squamous histology tumors, molecular testing will not be required in cases
where it is not part of the SoC.
- - Have experienced relapse or progression during or after treatment with standard
systemic therapy including platinum-based chemotherapy and/or immune checkpoint
inhibitor in the advanced/metastatic setting or discontinued from prior therapy
due to intolerance.
- - Participants must have received 1 to 3 lines of systemic treatment, which can
include anti-PD-1/PD-L1 therapy (if PD-L1 positive), chemotherapy, and
anti-angiogenic agents.
These treatments may be administered concurrently or
sequentially. Prior chemotherapy must be limited to fewer than 2 lines.
- - Cohort 1C:
- Have documented positive test results for an EGFR-sensitizing mutation
(EGFR-sensitizing mutation Exon 21-L858R and 19del).
- - Participants must have received one or two prior lines of systemic therapy for
advanced and/or metastatic disease, which must include treatment with an
approved EGFR Tyrosine Kinase Inhibitors (TKI), with at least one being a
third-generation EGFR TKI.
If there is no third-generation EGFR TKI approved as
part of SoC by local health authorities in a certain country,
failure/progression on any EGFR TKI is acceptable for eligibility.
- - Participants receiving an EGFR TKI at the time of signing informed consent may
continue to take the EGFR TKI until 5 days prior to Cycle 1 Day 1.
- - Chemotherapy is permitted only if it was administered in combination with an
EGFR TKI as part of a single line of therapy and as the initial (first line)
treatment for advanced/metastatic disease.
Participants must not have received
any other systemic therapies (such as chemotherapy, immunotherapy, or targeted
agents) for advanced/metastatic disease, unless those treatments were given in
combination with an EGFR TKI.
- - Have experienced progression during or after treatment or discontinued from
prior therapy due to intolerance.
- - Cohort 1D: Have histologically or cytologically confirmed diagnosis of unresectable
or metastatic acral/uveal/mucosal melanoma not amenable to local therapy.
- - Cohort 1D: Participants must have:
- Previously been treated with a PD-1 or PD-L1 inhibitor, if clinically indicated
and available per local SoC, and/or.
- - For participants with Human Leukocyte Antigen Alleles (HLA-A)*02:01
serotype-positive disease (only applicable for uveal melanoma), previously been
treated with tebentafusp-tebn if clinically indicated and available per local
SoC, and.
- - Experienced progression during or after the previous treatment or discontinued
from prior therapy due to intolerance.
- - Cohorts 1E and 1F (DDI): Have histologically or cytologically confirmed diagnosis of
unresectable or metastatic advanced solid tumor not amenable to ablative or curative
approach including, but not limited to:
- Cholangiocarcinoma, including tumors of the intra- and extrahepatic biliary
tract and gallbladder.
- - Hepatocellular carcinoma (HCC).
- - Endometrial carcinoma, excluding those classified as true sarcomas.
- - Pancreatic ductal adenocarcinoma (PDAC) (see below other related inclusion
criterion)
- Neuroendocrine tumor of pancreatic, gastrointestinal, lung, and thymus that is
well differentiated, Grade 1 to 3.
- - Cohort 1E and 1F (DDI): Have experienced disease progression on at least one and no
more than three lines of prior therapy or, for Cohort 1E only, discontinued from
prior therapy due to intolerance.
- - Cohort 1E and 1F (DDI): (For participants with PDAC only) Have received one or two
lines of systemic therapy for metastatic tumors, and have experienced progression or
intolerance to the treatment during or following therapy.
- - Cohort 2A: Have histologically or cytologically confirmed diagnosis of unresectable
or metastatic cutaneous melanoma not amenable to local therapy.
- - Cohort 2B: Have histologically or cytologically confirmed diagnosis of recurrent
unresectable or metastatic breast cancer that is documented as HER2-negative and
either hormone receptor (HR)-negative or HR-positive per American Society of
Clinical Oncology/College of American Pathologists guidelines.
Key Exclusion Criteria (applicable to all participants and all parts unless otherwise
specified):
- - Have a history of intolerance to treatment with a topoisomerase I inhibitor or
intolerance to an ADC that consists of a topoisomerase I inhibitor, including but
not limited to topotecan, irinotecan, and deruxtecan (e.g., severe diarrhea).
- - Have an uncontrolled concomitant or intercurrent illness that contra-indicates study
participation, limits compliance with study procedures or substantially increases
the risk of incurring adverse events, including:
- Bleeding diathesis or active hemorrhage,
- Active infection,
- Child-Pugh class B or C cirrhosis,
- Pulmonary disease with significant impact in lung function.
- - Oncologic emergencies or complications (e.g., malignant hypercalcemia, superior
vena cava syndrome, carcinoid syndrome that is unstable and with available
alternative therapies),
- Psychiatric or abuse condition.
- - Have LVEF <50% by either echocardiography or multi-gated acquisition (scanning)
within 28 days before randomization/enrollment.
- - Have clinically uncontrolled pleural effusion, ascites or pericardial effusion
requiring drainage, peritoneal shunt, or cell-free concentrated ascites reinfusion
therapy within 2 weeks prior to randomization/enrollment.
- - Have a history of (non-infectious) interstitial lung disease (ILD) /pneumonitis that
required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis
cannot be ruled out by imaging at screening.
Asymptomatic interstitial changes
caused by previous radiation therapy, chemotherapy, or other factors such as smoking
are acceptable.
- - Are a participant of child-bearing potential who are pregnant or breastfeeding or
are planning pregnancy within 225 days (~7.5 months) after receiving last dose of
BNT326 and within 6 months after last dose of BNT327, whichever is longer.
- - Are potentially fertile males, who are planning to father children during the study
or within 135 days (~4.5 months) after the last dose of BNT326 and within 6 months
after last dose of BNT327, whichever is longer.
- - Are subject to exclusion periods from another investigational study.
- - Participants with significant risks of hemorrhage or evidence of major coagulation
disorders as specified in the protocol.
- - Cohort 1E: Have histological diagnosis of fibrolamellar HCC, sarcomatoid HCC, or
mixed cholangiocarcinoma and HCC.
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
