Phase 0 Master Protocol for CIVO Intratumoral Microdosing of Anti-Cancer Therapies
Study Details
Study Description
Brief Summary
This is a multi-center, open-label Phase 0 Master Protocol designed to study the localized pharmacodynamics (PD) of anti-cancer therapies within the tumor microenvironment (TME) when administered intratumorally in microdose quantities via the CIVO device in patients with surface accessible solid tumors for which there is a scheduled surgical intervention. CIVO stands for Comparative In Vivo Oncology. Multiple substudies will include specified investigational agents and combinations to be evaluated.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Early Phase 1 |
Detailed Description
CIVO is a research tool composed of a hand-held single-use sterile injector coupled with fluorescent tracking microspheres called CIVO GLO that mark the sites of drug microdose injection, enabling rapid assessment of multiple oncology drugs or drug combinations simultaneously within a patient's tumor. Tumor responses to cancer treatments are highly context-specific and often involve complex interactions between the anti-cancer therapy, genetically diverse tumor cells, and a heterogeneous TME. This complexity is rarely modeled accurately in preclinical translational models of cancer. By utilizing intratumoral microdose injections with CIVO in advance of scheduled surgical intervention, this study will evaluate anti-cancer therapies directly in patients each with their own unique tumor genomic profile, intact TME, and immune system functional status. Because the platform delivers microdose amounts of each test agent or combination directly into the patient's tumor tissue, hypotheses can be tested earlier in the drug development process, consistent with the goals of the 2006 FDA Exploratory IND Guidance for Industry.
The CIVO device penetrates solid tumors and simultaneously delivers subtherapeutic microdoses of up to eight anti-cancer agents or combinations of anti-cancer agents co-injected with CIVO GLO into discrete regions of the tumor as drug columns. At the time of the planned surgical intervention (at least four hours to up to seven days after the CIVO microdose injection), the injected tumor tissue is then excised and tumor responses are assessed via histological staining of tumor cross-sections sampled perpendicular to each injection column. Co-injection with CIVO GLO enables identification of each injection site during resection as well as in tissues stained for analysis. This Phase 0 Master Protocol is aimed at distinguishing promising candidates earlier in the drug development process while also avoiding systemic toxicities associated with typical clinical exposures to these therapies.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: TAK-676, Carboplatin, 5-FU, & Paclitaxel Patients with HNSCC who are scheduled for surgical biopsy or tumor resection surgery will be injected at least four hours to up to four days prior to surgery using the CIVO device. Each needle of the CIVO device will deliver up to 8.3 microliters of solution, including a vehicle control (sterile saline) or subtherapeutic microdoses of TAK-676, carboplatin, 5-fluorouracil (5-FU), or paclitaxel as single agents or in combination. Each microdose is simultaneously injected in a columnar fashion through each of 8, 5, or 3 needles (in a device configuration determined by tumor dimensions) into a single solid tumor or effaced metastatic lymph node. |
Drug: TAK-676
Intratumoral microdose injection by the CIVO device.
Drug: Carboplatin
Intratumoral microdose injection by the CIVO device.
Other Names:
Drug: 5-FU
Intratumoral microdose injection by the CIVO device.
Other Names:
Drug: Paclitaxel
Intratumoral microdose injection by the CIVO device.
Other Names:
Combination Product: TAK-676 + Carboplatin
Intratumoral microdose injection by the CIVO device.
Combination Product: Carboplatin + Paclitaxel
Intratumoral microdose injection by the CIVO device.
Combination Product: Carboplatin + 5-FU
Intratumoral microdose injection by the CIVO device.
Combination Product: TAK-676 + Carboplatin + 5-FU
Intratumoral microdose injection by the CIVO device.
Combination Product: TAK-676 + Carboplatin + Paclitaxel
Intratumoral microdose injection by the CIVO device.
|
| Experimental: MK-0482, MK-4830, & Pembrolizumab Patients with HNSCC or STS who are scheduled for surgical biopsy or tumor resection surgery will be injected two to four days prior to surgery using the CIVO device. Each needle of the CIVO device will deliver up to 8.3 microliters of solution, including a vehicle control (sterile saline) or subtherapeutic microdoses of pembrolizumab as a single agent or in combination with MK-0482 or MK-4830. Each microdose is simultaneously injected in a columnar fashion through each of 8 needles into a single solid tumor or effaced metastatic lymph node. |
Biological: Pembrolizumab
Intratumoral microdose injection by the CIVO device.
Other Names:
Combination Product: MK-0482 + Pembrolizumab
Intratumoral microdose injection by the CIVO device.
Combination Product: MK-4830 + Pembrolizumab
Intratumoral microdose injection by the CIVO device.
|
Outcome Measures
Primary Outcome Measures
- Quantification of Cell Death and Immune Cell Biomarkers by IHC and In-Situ Hybridization [4 hours-7 days after microdose injection]
Quantification of biomarker-positive and biomarker-negative cells will be performed within the tumor microenvironment around each of the injection sites in each resected patient sample by IHC and ISH. An aggregate analysis of this quantification may be done across patient samples in each substudy to evaluate trends in tumor response. The biomarkers evaluated may include, but are not limited to biomarkers for cell death (e.g. cleaved caspase 3), T-cells (e.g. CD3, CD8/Granzyme B, CD4), natural killer (NK)/myeloid cells (e.g. CD56/Granzyme B, CD86, CD68, CD163), and proinflammatory cytokines (e.g., interferon gamma, tumor necrosis factor alpha, interferon gamma-induced protein 10).
Secondary Outcome Measures
- Number of Patients with Adverse Events [Up to 28 days after microdose injection]
Relationship of AE to study drug(s) or CIVO device will be determined using an AE Relatedness Grading System.
Eligibility Criteria
Criteria
*This list is representative of study inclusion/exclusion criteria. Each substudy may include variations on these criteria.
Inclusion Criteria:
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Ability and willingness to comply with the study's visit and assessment schedule.
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Male or female ≥ 18 years of age at Visit 1 (Screening).
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Pathologic diagnosis of [solid tumors] indicated in the relevant substudy(ies).
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Ability and willingness to provide written informed consent. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
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At least one lesion (primary tumor, recurrent tumor, or effaced metastatic lymph node) ≥ 2 cm in the shortest diameter that is surface accessible for CIVO injection that may be guided by ultrasound if appropriate and for which there is a planned surgical intervention. Treatment plan my include adjuvant radiation or chemotherapy and patients should have no medical contraindication to surgery.
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Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
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Female patients who:
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Are postmenopausal for at least one year before the screening visit, OR
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Are surgically sterile, OR
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Are of childbearing potential who agree to practice a highly effective method of contraception from the time of signing the Informed Consent Form (ICF) and during study participation OR agree to completely abstain from heterosexual intercourse.
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Agree to refrain from donating ova during study participation.
Male patients, even if surgically sterile (i.e., status post-vasectomy), who:
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Agree to practice effective barrier contraception from the time of signing the ICF and during study participation OR agree to completely abstain from heterosexual intercourse.
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Agree to refrain from donating sperm during study participation.
Exclusion Criteria:
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Tumors or effaced nodes that are anticipated by the Investigator to lack a sufficient volume of viable tumor tissue (based on available pre-operative imaging, pre-injection ultrasound imaging, or pathology reports) for CIVO injection due to size, location, necrosis, cysts, excessive stroma, or fibrosis.
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Patients who have received neoadjuvant therapy associated with the surgical intervention described in Inclusion Criterion #5.
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Tumors near or involving critical structures for which, in the opinion of the treating clinician, injection would pose undue risk to the patient.
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Female patients who are:
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Both lactating and breastfeeding, OR
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Have a positive β-subunit human chorionic gonadotropin (β-hCG) pregnancy test at screening verified by the Investigator.
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Any uncontrolled intercurrent illness, condition, serious medical or psychiatric illness, or circumstance that, in the opinion of the Investigator, could interfere with adherence to the study's procedures or requirements, or otherwise compromise the study's objectives.
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Patients with a history of concurrent second cancers requiring active, ongoing systemic treatment.
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Patients with active autoimmune diseases requiring treatment.
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Patients with known human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) with uncontrolled viral load and CD4 less than 200, or known chronic hepatitis B/C.
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Patients that have received a live vaccine within 4 weeks of the baseline/screening visit.
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Use of any of the following ≤ 2 weeks prior to CIVO injection:
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Chronic systemic immunosuppressive therapy or corticosteroids (e.g., prednisone or equivalent exceeding a total dose of 140 mg over the last 14 days). Intranasal, inhaled, topical, or local corticosteroid injections (e.g., intra-articular injection), or steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication) are exceptions to this criterion.
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Biological response modifiers for treatment of active autoimmune disease.
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Hematopoietic growth factors.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | LSU Health Sciences Center - Shreveport | Shreveport | Louisiana | United States | 71115 |
| 2 | Montefiore Medical Center | Bronx | New York | United States | 10467 |
| 3 | Wake Forest Baptist Health | Winston-Salem | North Carolina | United States | 27157 |
| 4 | Oregon Health & Science University (OHSU) | Portland | Oregon | United States | 97239 |
| 5 | University of Pennsylvania | Philadelphia | Pennsylvania | United States | 19107 |
Sponsors and Collaborators
- Presage Biosciences
- Takeda
- Merck Sharp & Dohme LLC
Investigators
- Study Director: Medical Director, Presage Biosciences
Study Documents (Full-Text)
None provided.More Information
Publications
- Dey J, Kerwin WS, Grenley MO, Casalini JR, Tretyak I, Ditzler SH, Thirstrup DJ, Frazier JP, Pierce DW, Carleton M, Klinghoffer RA. A Platform for Rapid, Quantitative Assessment of Multiple Drug Combinations Simultaneously in Solid Tumors In Vivo. PLoS One. 2016 Jun 30;11(6):e0158617. doi: 10.1371/journal.pone.0158617. eCollection 2016.
- Frazier JP, Bertout JA, Kerwin WS, Moreno-Gonzalez A, Casalini JR, Grenley MO, Beirne E, Watts KL, Keener A, Thirstrup DJ, Tretyak I, Ditzler SH, Tripp CD, Choy K, Gillings S, Breit MN, Meleo KA, Rizzo V, Herrera CL, Perry JA, Amaravadi RK, Olson JM, Klinghoffer RA. Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation. Cancer Res. 2017 Jun 1;77(11):2869-2880. doi: 10.1158/0008-5472.CAN-17-0084. Epub 2017 Mar 31.
- Gundle KR, Deutsch GB, Goodman HJ, Pollack SM, Thompson MJ, Davis JL, Lee MY, Ramirez DC, Kerwin W, Bertout JA, Grenley MO, Sottero KHW, Beirne E, Frazier J, Dey J, Ellison M, Klinghoffer RA, Maki RG. Multiplexed Evaluation of Microdosed Antineoplastic Agents In Situ in the Tumor Microenvironment of Patients with Soft Tissue Sarcoma. Clin Cancer Res. 2020 Aug 1;26(15):3958-3968. doi: 10.1158/1078-0432.CCR-20-0614. Epub 2020 Apr 16.
- Klinghoffer RA, Bahrami SB, Hatton BA, Frazier JP, Moreno-Gonzalez A, Strand AD, Kerwin WS, Casalini JR, Thirstrup DJ, You S, Morris SM, Watts KL, Veiseh M, Grenley MO, Tretyak I, Dey J, Carleton M, Beirne E, Pedro KD, Ditzler SH, Girard EJ, Deckwerth TL, Bertout JA, Meleo KA, Filvaroff EH, Chopra R, Press OW, Olson JM. A technology platform to assess multiple cancer agents simultaneously within a patient's tumor. Sci Transl Med. 2015 Apr 22;7(284):284ra58. doi: 10.1126/scitranslmed.aaa7489.
- Moreno-Gonzalez A, Olson JM, Klinghoffer RA. Predicting responses to chemotherapy in the context that matters - the patient. Mol Cell Oncol. 2015 Jun 10;3(1):e1057315. doi: 10.1080/23723556.2015.1057315. eCollection 2016 Jan.
- PBI-MST-01