Trial Title:
PT886 For Treatment of Patients With Metastatic/Advanced Gastric, Gastroesophageal Junction and Pancreatic Adenocarcinoma (the TWINPEAK Study)
NCT ID:
NCT05482893
Condition:
Gastric or Gastroesophageal Junction Adenocarcinoma
Pancreatic Ductal Adenocarcinoma
Conditions: Official terms:
Adenocarcinoma
Leucovorin
Paclitaxel
Gemcitabine
Pembrolizumab
Capecitabine
Oxaliplatin
Fluorouracil
Albumin-Bound Paclitaxel
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
PT886
Description:
PT886 monotherapy, a novel bispecific antibody that targets Claudin 18.2 and CD47.
Arm group label:
Combination Expansion with Chemotherapy
Arm group label:
Combination Expansion with KEYTRUDA® (pembrolizumab)
Arm group label:
Dose Escalation
Arm group label:
Dose Expansion
Intervention type:
Drug
Intervention name:
Paclitaxel
Description:
Chemotherapy as a combination partner to PT886 in Part C: Cohort 1
Arm group label:
Combination Expansion with Chemotherapy
Intervention type:
Drug
Intervention name:
Gemcitabine
Description:
Chemotherapy as a combination partner to Abraxane and PT886 in Part C: Cohort 2
Arm group label:
Combination Expansion with Chemotherapy
Intervention type:
Drug
Intervention name:
Abraxane
Description:
Chemotherapy as a combination partner to Gemcitabine and PT886 in Part C: Cohort 2
Arm group label:
Combination Expansion with Chemotherapy
Intervention type:
Drug
Intervention name:
KEYTRUDA® (pembrolizumab)
Description:
Immune checkpoint inhibitor as a combination partner to PT886 in Part D: Cohort 3, 4, and
5.
Arm group label:
Combination Expansion with KEYTRUDA® (pembrolizumab)
Intervention type:
Drug
Intervention name:
Oxaliplatin
Description:
Chemotherapy as a combination partner to KEYTRUDA® (pembrolizumab) and PT886 in Part D:
Cohort 4
Arm group label:
Combination Expansion with KEYTRUDA® (pembrolizumab)
Intervention type:
Drug
Intervention name:
Leucovorin
Description:
Chemotherapy as a combination partner to KEYTRUDA® (pembrolizumab) and PT886 in Part D:
Cohort 4
Arm group label:
Combination Expansion with KEYTRUDA® (pembrolizumab)
Intervention type:
Drug
Intervention name:
Fluorouracil
Description:
Chemotherapy as a combination partner to KEYTRUDA® (pembrolizumab) and PT886 in Part D:
Cohort 4
Arm group label:
Combination Expansion with KEYTRUDA® (pembrolizumab)
Intervention type:
Drug
Intervention name:
Capecitabine
Description:
Chemotherapy as a combination partner to KEYTRUDA® (pembrolizumab) and PT886 in Part D:
Cohort 4
Arm group label:
Combination Expansion with KEYTRUDA® (pembrolizumab)
Summary:
This is a first-in-human, Phase 1/2, open-label, dose escalation and dose expansion and
combination study designed to evaluate the safety, tolerability, pharmacokinetics,
pharmacodynamics, and preliminary efficacy of PT886.
Patients with the following tumor types will be eligible for screening: unresectable or
metastatic gastric adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma, and
pancreatic ductal adenocarcinoma (PDAC).
Criteria for eligibility:
Criteria:
Inclusion Criteria
Patients are eligible to be included in the study only if all the following criteria
apply:
1. 18 years or older and able to sign informed consent and comply with the protocol.
2. Measurable disease as defined by RECIST V1.1 criteria for solid tumors. Lesions
situated in a previously irradiated area are considered measurable if progression
has been demonstrated in such lesions. Patients with measurable or non-measurable
disease are allowed to participate in Part A of the study.
3. Part A and Part B: Histologically or cytologically confirmed unresectable advanced
or metastatic solid gastric, gastroesophageal junction (GEJ), or pancreatic tumors
(adenocarcinomas type) previously treated for advanced (metastatic or unresectable)
disease or for which treatment is not available or not tolerated.
In Parts B, C and D, patients must present with ≥ 10% CLDN18.2 positive TC in their
tumor tissue, with the exception of Cohort 2 (Part C) and Cohort 4 (Part D). For
Cohorts 2 and 4. This cutoff may change based off emerging data. Archival tissue can
be used to assess the expression level of CLDN18.2. For archival tissue older than
12 months, we recommend a fresh biopsy. For Part D, Cohort 5, patients must have ≥
10% CLDN18.2 positive TC score in their tumor biopsy sample acquired after patients
completed their prior zolbetuximab treatment.
Part C, Cohort 1: Patients with metastatic or advanced (m/a) GC/GEJ-C, that have
progressed under 1L SOC chemotherapy +/- ICI, are treatment naïve to CLDN18.2
targeting agents, and are eligible for 2L SOC treatment. HER2+ patients are
eligible. HER2+ patients may preferably continue with their HER2 targeted treatment
due to the availability of a 2L targeted treatment option, such as trastuzumab
deruxtecan if they are still HER2 positive. Patients who do not have access to 2L
targeted treatment and are still HER2+ are eligible as long they present with ≥ 10%
CLDN18.2 positive TC in their tumor tissue.
Part C, Cohort 2: PDAC patients, that are treatment naïve for their m/a disease and
have no contra indication to receive Gemcitabine plus Abraxane (nab-paclitaxel).
Part D, Cohort 3: Patients with m/a GC/GEJ-C who have progressed under 1L or 2L SOC
chemotherapy +/- ICI and are treatment naïve to CLDN18.2 targeting agents. Patients
who were initially HER2+ and have exhausted their HER2 targeted therapy or where
trastuzumab deruxtecan is not available, are equally eligible to be enrolled into
this cohort and do not require a fresh biopsy. Patients will receive PT886 combined
with pembrolizumab.
Part D, Cohort 4: Patients with m/a HER2 negative GC/GEJ-C, that are treatment naïve
for their m/a disease.
Part D, Cohort 5: Patients with m/a GC/GEJ-C, that have progressed under 1L SOC
chemotherapy, and zolbetuximab treatment, and are treatment naïve to pembrolizumab
or other ICI therapy for their m/a disease. Patients must present with ≥ 10%
CLDN18.2 positive TC in their tumor cells following their zolbetuximab treatment.
4. Biopsies:
Able to provide a formalin fixed, paraffin embedded (FFPE) tumor tissue sample
(preferably fresh biopsy or if not possible, archival tissue) to be assessed for
CLDN18.2 expression and other biomarkers. Biopsy must be excisional, incisional, or
core needle. Fine needle aspiration is insufficient. This biopsy may not be done if
the biopsy poses a risk to the patient and/or per the Investigators discretion.
- Archival tissue can be used to assess the expression level of CLDN18.2 for all
Parts. In Part D for Cohort 5, a newly acquired fresh biopsy may be requested
unless a biopsy was taken after completion of zolbetuximab treatment.
- If the archival tissue is older than 12 months, we recommend a newly acquired
fresh biopsy. For Parts C and D, willingness to have an on-treatment biopsy in
patients that have stable disease or partial response at week 16, if deemed
clinically feasible by the Investigator.
5. ECOG performance status of 0 or 1.
6. Adequate organ function confirmed at screening and within 96 hours of initiating
treatment, as evidenced by:
- Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
- Hemoglobin (Hgb) ≥ 9.0 g/dL1 (RBC transfusions not permitted in the 4-week
period before enrollment).
- Platelets (plt) ≥ 100 × 109/L
- AST/SGOT and ALT/SGPT ≤ 2.5 × Upper Limit of Normal (ULN) or ≤ 5.0 × ULN if
liver metastases are present.
- Total bilirubin ≤ 1.5 × ULN without liver metastases (or < 3.0 x ULN if liver
metastases are present).
- Calculated creatinine clearance ≥ 30 mL/min (Cockcroft Gault formula). 1
Criteria must be met without packed red blood cell (pRBC) transfusion within
the prior 2 weeks. Participants can be on stable dose of erythropoietin (≥
approximately 3 months).
7. Resolution of all acute adverse events resulting from prior cancer therapies to
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE V5.0) Grade ≤ 1 or baseline (except alopecia or neuropathy (< Grade 3)).
Patients with endocrine-related AEs Grade ≤ 2 requiring treatment or hormone
replacement may be eligible.
8. Negative serum pregnancy test within 72 hours before starting study treatment in all
pre-menopausal women, and women < 24 months after the onset of menopause (had a
menstrual period in past 24 months) and are of childbearing potential (women who
underwent hysterectomy or bilateral oophorectomy do not need a pregnancy test).
9. Must agree to use effective contraceptive methods to avoid pregnancy (including male
and female patients and partners of study patients) during the study and until at
least 7 months after the last dose of study treatment. Examples of contraceptive
methods with a failure rate of < 1% per year include bilateral tubal ligation, male
sterilization, established, proper use of hormonal contraceptives that inhibit
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration
of the clinical trial and the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g., calendar, ovulation, symptom-thermal, or post-ovulation methods)
and withdrawal are not acceptable methods of contraception.
10. Life expectancy >3 months.
Exclusion Criteria
Patients are excluded from the study if any of the following criteria apply:
1. Women who are pregnant or lactating.
2. Women of child-bearing potential (WOCBP) who do not use adequate birth control.
3. Has an active autoimmune disease that has required systemic treatment in the past 2
years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency) is not considered a form of systemic treatment and is allowed.
4. Condition requiring systemic treatment with either corticosteroids or other
immunosuppressive medications within 14 days prior to study treatment.
Corticosteroids doses equivalent to Prednisone 10 mg per day or less are allowed
(see Criteria 3 for exceptions), or a single application of up to 8 mg dexamethasone
i.v. over 30 minutes prior to dosing the first two PT886 doses, in individual cases.
5. Patients with a history of (non-infectious) pneumonitis that required steroids,
current pneumonitis, or have a history of interstitial lung disease. History of
COVID-19 pneumonia with fibrotic changes.
6. Patients with untreated brain or central nervous system (CNS) metastases or
brain/CNS metastases that have progressed (e.g., evidence of new or enlarging brain
metastasis or new neurological symptoms attributable to brain/CNS metastases).
Note: Patients with treated brain metastases that are off corticosteroids and have
been clinically stable for 28 days are eligible for enrollment.
7. Patients with a known concurrent malignancy that is progressing or has required
treatment for active disease within the previous 24 months. Exceptions include basal
cell carcinoma of the skin, carcinoma in situ of the cervix or other noninvasive or
indolent malignancy that has previously undergone potentially curative therapy.
8. Patients who have received an investigational product, 4 weeks or 5 half-lives,
whichever is shorter, prior to start of study drug during Part A and Part B. Prior
investigational treatment for m/a disease is not allowed during Part C and D, with
the exception of Part D, Cohort 5, where prior zolbetuximab treatment is allowed.
9. Prior CLDN18.2 or CD47 targeting therapies, or SIRPα (signal regulatory protein
alpha) targeting agents. For Part D, Cohort 5, prior treatment with zolbetuximab is
allowed.
10. Patients that have received a live-virus vaccination within 30 days of planned
treatment start.
11. Impaired cardiac function or significant diseases, including but not limited to any
of the following:
1. LVEF < 45% as determined by MUGA scan or ECHO.
2. Congenital long QT syndrome.
3. QTcF ≥ 480 msec on screening ECG.
4. Unstable angina pectoris ≤ 3 months prior to starting study drug.
5. Acute myocardial infarction or stroke ≤ 3 months prior to starting study drug.
12. Patients with uncontrolled hypertension (defined as blood pressure of ≥ 150 mmHg
systolic and/or ≥ 90 mmHg diastolic at Screening).
13. Prior hemolytic anemia or Evans Syndrome in the last 3 months.
14. RBC transfusion during the 4-week period prior to enrollment. RBC transfusions are
not permitted during the screening period and prior to enrollment to meet the
hemoglobin inclusion criteria.
15. Patients who have ≥ Grade 3 neuropathy.
16. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
uncontrolled hypertriglyceridemia [triglycerides > 500 mg/dL], or active infection
requiring parenteral treatment) that could cause unacceptable safety risks or
compromise compliance with the protocol.
17. Patients who have received chemotherapy, ≤ 5 half-lives or 3 weeks, whichever is
shorter (6 weeks for nitrosourea or mitomycin-C), targeted therapy, or immunotherapy
within 4 weeks prior to starting study drug.
18. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field
radiation for palliation ≤ 2 weeks prior to starting study drug or who have not
recovered from adverse events of prior therapy. Patients with a history of radiation
pneumonitis are not eligible.
Note: Patients must have recovered from all radiation-related toxicities and not
require corticosteroids. A 1-week washout is permitted for palliative radiation (≤ 2
weeks of radiotherapy) to non-CNS disease.
19. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or
who have not recovered from adverse events of prior therapy.
20. Active gastric perforation, pyloric obstruction, complete biliary obstruction,
complete or incomplete intestinal obstruction requiring clinical intervention, or
pleural effusion or peritoneal effusion requiring clinical intervention.
21. Patients who are currently receiving treatment with therapeutic doses of warfarin
sodium (Coumadin®) or any other coumarin-derivative anticoagulants (Other
anticoagulants such as anti-thrombin or factor X inhibitors are allowed).
22. Patients who have experienced any thromboembolic event such as deep vein thrombosis
(DVT) or pulmonary embolism in the past 6 months.
23. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not
mandatory; patients with well controlled HIV might be enrolled per Investigator's
discretion). HIV-infected patients with a history of Kaposi sarcoma and/or
Multicentric Castleman Disease are not eligible. HIV infected patients must be on
antiretroviral therapy (ART) and have a well-controlled HIV infection/disease
defined as:
1. Patients on ART must have a CD4+ T-cell count >350 cells/mm3 at time of
screening.
2. Patients on ART must have achieved and maintained virologic suppression defined
as confirmed HIV RNA level below 50 copies/mL or the lower limit of
qualification (below the limit of detection) using the locally available assay
at the time of screening and for at least 12 weeks prior to screening.
3. Patients on ART must have been on a stable regimen, without changes in drugs or
dose modification, for at least 4 weeks prior to study entry (Day 1).
24. Evidence of active infection with Hepatitis B or Hepatitis C that is not adequately
controlled. (For patients with known prior history of Hepatitis B (defined as hBsAg
reactive) or Hepatitis C (defined as HCV RNA [qualitative] is detected), enrollment
may be allowed per Investigator's discretion). Note: No testing for Hepatitis B and
Hepatitis C is required unless mandated by a local health authority.
- Patients who are hBsAg positive are eligible if they have received HBV
antiviral therapy for at least 4 weeks and have undetectable HBV viral load
prior to randomization. Patients should remain on anti-viral therapy throughout
study intervention and follow local guidelines for HBV anti-viral therapy post
completion of study intervention.
- Patients with history of HCV infection are eligible if HCV viral load is
undetectable at screening. Patients must have completed curative anti-viral
therapy at least 4 weeks prior to randomization.
25. Has allergies or hypersensitivity (≥ Grade 3) to PT886 and/or any of its excipients
(polysorbate 80, L-histidine, Sucrose, L-arginine-HCl), or to pembrolizumab and/or
any of its excipients.
26. Has had an allogeneic tissue/solid organ transplant.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
USC Norris Comprehensive Cancer Center
Address:
City:
Los Angeles
Zip:
90033
Country:
United States
Status:
Recruiting
Contact:
Phone:
323-865-3000
Investigator:
Last name:
Diana Hanna, MD
Email:
Principal Investigator
Facility:
Name:
Sarah Cannon Research Institute (SCRI)
Address:
City:
Denver
Zip:
80218
Country:
United States
Status:
Recruiting
Contact:
Phone:
720-754-2610
Investigator:
Last name:
Jason Henry, MD
Email:
Principal Investigator
Facility:
Name:
Dana-Farber Cancer Institute (DFCI)
Address:
City:
Boston
Zip:
02215
Country:
United States
Status:
Recruiting
Investigator:
Last name:
Harshabad Singh, MD
Email:
Principal Investigator
Facility:
Name:
MD Anderson Cancer Center, GI Medical Oncology Dept
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Contact:
Last name:
Z. Esra Cobanoglu, MD
Phone:
832-817-4012
Email:
ZECobanoglu@mdanderson.org
Investigator:
Last name:
Michael Overman, MD
Email:
Principal Investigator
Facility:
Name:
NEXT Oncology
Address:
City:
Fairfax
Zip:
22031
Country:
United States
Status:
Recruiting
Contact:
Last name:
Blake Patterson
Phone:
(703) 783-4505
Email:
bpatterson@nextoncology.com
Investigator:
Last name:
Alexander Spira, MD, PhD, FACP
Email:
Principal Investigator
Start date:
March 15, 2023
Completion date:
April 2026
Lead sponsor:
Agency:
Phanes Therapeutics
Agency class:
Industry
Collaborator:
Agency:
Merck Sharp & Dohme LLC
Agency class:
Industry
Source:
Phanes Therapeutics
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05482893