Overview

Phase II Study of SBRT/Olaparib Followed by Pembrolizumab/Olaparib in Gastric Cancers

Status:
Not yet recruiting
Trial end date:
2028-12-01
Target enrollment:
0
Participant gender:
All
Summary
This study is an open-label, phase II study with a safety lead-in to assess the response rate of induction olaparib and stereotactic beam radiotherapy (SBRT) followed by combination olaparib/pembrolizumab in patients with metastatic gastric and GEJ cancers after at least one of therapy.
Phase:
Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
University of Colorado, Denver
Collaborator:
Merck Sharp & Dohme LLC
Treatments:
Olaparib
Pembrolizumab
Criteria
Inclusion Criteria:

1. Provision to sign and date the consent form.

2. Participant must be ≥ 18 years of age

3. Histologically confirmed metastatic gastric or GEJ adenocarcinoma that is amenable to
biopsy either at primary or metastatic site.

4. Patient must consent at initiation of study to serial tumor biopsies during study.
Irradiated lesions will not be considered for biopsy. For baseline biopsy, available
archived tumor tissue of a metastatic tumor collected up to 28 days prior to
registration is acceptable. If, after patient consent, the tumor is deemed
inaccessible, the biopsy is not in the subject's best interest per investigator
discretion, or the patient refuses biopsy during course of the study, patients will be
allowed to remain on study.

5. Participant must have a primary tumor or a single metastatic site amenable to
radiation in: the stomach, esophagus, liver, lungs, pancreas, thoracic/abdominal LNs,
or soft tissues. Of note - sites of disease planned to be biopsied should not be
radiated.

6. Participant must have at least one radiographically-confirmed index lesion that will
not undergo RT and is measurable based on RECIST v1.1.

7. Homologous recombination deficiency cohort: pre-identified presence of somatic or
germline deleterious mutation, as determined by NGS only, in at least one gene
critical to DNA repair through homologous recombination, including but not limited to:
ARID1A, ATM, ATRX, MRE11A, NBN, PTEN, RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1,
FANCA/C/D2/E/F/G/L, PALB2, WRN, CHEK2, CHEK1, BAP1, FAM175A, SLX4, MLL2 or XRCC.

1. All patients must undergo NGS testing in a CLIA certified, CAP tested and
bioinformatics-validated testing lab PRIOR to protocol treatment, to determine
which cohort they are eligible for - HRD versus HR proficient. The testing may
have been done at any time prior to enrollment.

2. For patients within whom a deleterious mutation in the homologous recombination
pathway is found, the determination of a deleterious mutation must be supported
in the documentation included in the testing, and should include clinical, or
pre-clinical literature to support the finding that a specific mutation results
in impaired function of the gene, and thus impaired DNA repair through homologous
recombination. Variants of unknown significance will not be eligible.

3. Patients with germline deleterious mutations may have been identified at any time
point prior to inclusion in the protocol and do NOT need to have this genetic
testing repeated regardless of time frame and intervening therapy.

8. Participants must have received at least one line of therapy including a
fluoropyrimidine and platinum drug. For participants with HER2+ tumors, they must have
received trastuzumab. Adjuvant therapy does not count toward first-line therapy unless
patient recurs within 6 months of completion.

9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

10. Participants must have the ability to swallow whole pills and liquids at the Screening
Visit and, in the investigator's judgement, for the duration of the study.

11. Have adequate organ function as defined in Table 1:

Table 1: Adequate Organ Function Laboratory Values:

System: Laboratory Value:

Hematological

Absolute neutrophil count (ANC) ≥1500/μL Platelets ≥100 000/μL Hemoglobin ≥9.0 g/dL or
≥5.6 mmol/La

Renal

Creatinine OR Measured or calculated creatinine ≤1.5 × ULN OR ≥30 mL/min for
participant with creatinine levels >1.5 × institutional ULN clearance (GFR can also be
used in place of creatinine or CrCl)

Hepatic

Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total
bilirubin levels >1.5 × ULN AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for
participants with liver metastases)

Coagulation

International normalized ratio (INR) OR ≤1.5 × ULN unless participant is receiving
anticoagulant therapy as long as PT or aPTT is within therapeutic range of prothrombin
time (PT) intended use of anticoagulants Activated partial thromboplastin time (aPTT)

≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT
is within therapeutic range of intended use of anticoagulants

12. Participant receiving corticosteroids, for reasons other than radiation related
toxicities, may continue as long as their dose is stable (meaning no increase or on
tapering dose) for least 4 weeks prior to initiating protocol therapy.

13. Female participants are eligible if they are: not pregnant (within 28 days prior to
start of study treatment - see Appendix 3), not breastfeeding, and at least one of the
following conditions applies: a.) Not a woman of childbearing potential (WOCBP) as
defined in Appendix 3 OR b.) A WOCBP who agrees to follow contraceptive guidance
during the treatment period and for at least 120 days after the last dose of study
treatment.

14. Male participants must agree to use a contraception as detailed in Appendix 3 of this
protocol during the treatment period and for at least 120 days after the last dose of
study treatment and refrain from donating sperm during this period.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation
in this study:

1. Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to allocation.

1. Note: Participants must have recovered from all AEs due to previous therapies to
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.

2. Note: If participant received major surgery within 4 weeks, they must have
recovered adequately from the toxicity and/or complications from the intervention
prior to starting study treatment.

2. Has received prior radiotherapy within 2 weeks of start of study treatment.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids specifically for radiation toxicities, and not have had radiation
pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of
radiotherapy) to non-CNS disease.

3. Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. Note:
Vaccines for SARS CoV- 2 will be permitted before and during the course of study.

4. Is currently participating in, or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study treatment. Note: Participants who have entered the follow-up phase of an
investigational study may participate as long as it has been 4 weeks after the last
dose of the previous investigational agent.

5. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.

6. Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
cervical cancer in situ) that have undergone potentially curative therapy are not
excluded

7. Has known active CNS metastases and/or carcinomatous meningitis that requires ongoing
treatment or are found to be progressing. Participants with previously treated brain
metastases may participate provided they are radiologically stable, i.e. without
evidence of progression for at least 4 weeks by repeat imaging (note that the repeat
imaging should be performed during study screening), clinically stable and without
requirement of steroid treatment for at least 14 days prior to first dose of study
treatment.

8. Has severe hypersensitivity (≥Grade 3) to pembrolizumab or olaparib and/or any of its
excipients.

9. Participant must not have impairment of gastrointestinal (GI) function or GI disease
that may significantly alter the absorption of the study drugs (e.g., ulcerative
diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small
bowel resection).

10. Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

11. Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.

12. Has an active infection requiring systemic therapy.

13. Has a known history of Human Immunodeficiency Virus (HIV).