Study of DNA Damage, Angiogenesis, and PD-L1 Inhibitors in Advanced Solid Tumors

NCT03851614 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: DAPPER-001
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase 2, single-centre, randomized, multi-cohort trial of subjects with advanced Mismatch Repair Proficient Colorectal Cancer (MMRp-CRC), Pancreatic Adenocarcinoma (PA), and Leiomyosarcoma (LMS). Subjects will be stratified based on their primary malignancy and enrolled into one of the following cohorts:

• Cohort A: olaparib and durvalumab.
• Cohort B: cediranib and durvalumab. Subjects will receive durvalumab through an intravenous line every 4 weeks. If subjects are assigned to the olaparib group, then they will take this pill twice a day continuously. If subjects are assigned to the cediranib group, then they will take this pill once a day for 5 consecutive days, and then have 2 consecutive days off, every week. Subjects will be enrolled in this trial to evaluate the changes in genomic and immune biomarkers in tumor, peripheral blood and stool samples, in addition to changes in radiomic profiles. About 90 people (45 subjects in each cohort) will be enrolled into this study at the Princess Margaret Cancer Centre.

Conditions

Mismatch Repair Proficient Colorectal Cancer; Pancreatic Adenocarcinoma; Leiomyosarcoma

Outcome Measures

Primary Outcomes (1)

• Changes in genomic and immune biomarkers that will be measured in the baseline biopsy and the first on-treatment biopsy by applying a log-transformation and the t-test.

  If a departure from the normal distribution will be noticed for the distributions of the CD8 and CD4 then a log-transformation will be applied. The CD8 and CD4 will be compared between responders and non-responders by applying the t-test. Subgroup analysis based on the site will also be attempted.

  3 years

Secondary Outcomes (6)

• Overall response rate (ORR)

  3 years

• Clinical benefit rate (CBR)

  3 years

• Progression-free survival (PFS)

  3 years

• Overall survival (OS)

  3 years

• Antitumor activity based on iRECIST

  3 years

Study Arms (2)

Cohort A

EXPERIMENTAL

Olaparib (given orally at a dose of 300 mg twice a day) in combination with Durvalumab (given intravenously at a dose of 1500 mg every 4 weeks)

Biological: Durvalumab; Drug: Olaparib

Cohort B

EXPERIMENTAL

Cediranib (given orally at a dose of 20 mg daily, 5 days on 2 days off) in combination with Durvalumab (given intravenously at a dose of 1500 mg every 4 weeks)

Biological: Durvalumab; Drug: Cediranib

Interventions

Durvalumab BIOLOGICAL

Durvalumab is a human immunoglobulin G (IgG)1 kappa monoclonal antibody directed against human PD-L1. Durvalumab selectively binds human PD-L1 with high affinity and blocks its ability to bind to PD-1 and cluster of differentiation (CD)80. The fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the constant domain of the IgG1 heavy chain that reduces binding to the complement component C1q and the Fc gamma receptors responsible for mediating antibody dependent cell mediated cytotoxicity.

Also known as: Imfinzi

Cohort A; Cohort B

Olaparib DRUG

Olaparib (AZD2281) is a potent oral poly Poly (ADP-ribose) Polymerase (PARP) enzyme inhibitor (PARP-1, -2 and -3) that is being developed as an oral therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy and other anti-cancer agents. Olaparib specifically traps PARP1 and PARP2 enzymes at sites of damaged DNA; the trapped PARP1- or PARP2-DNA complex is cytotoxic and produces clinical response. Although olaparib also binds to PARP3, recent investigations have suggested PARP-3 inhibition does not contribute towards anti-cancer activity.

Also known as: Lynparza, AZD2281

Cohort A

Cediranib DRUG

Cediranib (AZD2171) is a potent oral small molecule Vascular Endothelial Growth Factor (VEGF) receptor tyrosine kinase inhibitor, specifically inhibiting all three VEGF receptors (VEGFR-1, -2 and -3). It has additional inhibitory activity against stem cell factor receptor tyrosine kinase, and less potency against platelet-derived growth factor receptor tyrosine kinases. Cediranib exerts its anti-angiogenic property by competitively inhibiting the ATP binding site on the VEGF receptors.

Also known as: AZD2171

Cohort B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent
• Age ≥18
• ECOG 0-1
• Have histologically/cytologically-documented, locally-advanced, or metastatic mismatch repair proficient colorectal cancer (MMRp-CRC), pancreatic adenocarcinoma (PA), or leiomyosarcoma (LMS) that is incurable and has either (a) failed prior standard therapy, (b) for which no standard therapy exists, or (c) standard therapy is not considered appropriate by the subject and treating physician
• Allowable: prior immune-oncology therapy, no maximal limit to the number of prior lines of systemic therapy for advanced or metastatic disease. All prior anti-neoplastic systemic therapy, including immune-oncology, must have a 4 week wash out period. There is no limit to the number of prior anti-neoplastic systemic treatments used before trial enrolment
• Must have at least 1 tumor site that is amendable to tumor biopsy
• Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 4 weeks (28 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided will not be eligible for this study. Subjects who have archival tissue available, not older than 6 months and with no intervening therapies from the day of the biopsy and the initiation of the study, will also be requested to also submit this sample, but are still required to undergo a pre-treatment biopsy.
• Consent to provide archival tumor tissue for correlative biomarker studies
• Must have at least 1 tumor site that is RECISTv1.1 measurable by CT or MRI scan. A previously irradiated lesion can be considered a target lesion if the lesion is well defined, measurable and there is objective evidence of progression following radiotherapy. The biopsy lesion cannot be the same as the target lesion
• Life expectancy ≥ 16 weeks from proposed first dose date
• Female subject of childbearing potential should have two negative pregnancy tests as verified by the investigator prior to starting any investigational product therapy: serum pregnancy test at screening and negative serum or urine pregnancy test on Cycle 1, Day 1 prior to treatment, and confirmed prior to each subsequent cycle of treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. They must agree to pregnancy testing after the last dose of durvalumab, olaparib or cediranib. This applies even if the subject practices complete abstinence from heterosexual contact
• Females of childbearing potential who are sexually active with a non-sterilized male partner must agree to practice true abstinence or at least two effective methods of contraception from 28 days prior to starting durvalumab, olaparib or cediranib, and agree to continue using such precautions while taking durvalumab, olaparib or cediranib and for 90 days following the last dose of investigational product(s). Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. They must also refrain from egg cell donation and breastfeeding during study participation and for at least 90 days after the final dose of investigational product(s)
• Non-sterilized males who are sexually active with a female partner of childbearing potential must agree to use at least two effective methods of contraception from Day 1 through 90 days after receipt of the final dose of investigational product(s). In addition, they must refrain from sperm donation for 90 days after the final dose of investigational product(s). Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential
• Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
• Adequately controlled thyroid function, with no symptoms of thyroid dysfunction. Elevated thyroid stimulating hormone (TSH) with normal free T3 and free T4 are allowed; subjects on thyroid replacement therapy are allowed

You may not qualify if:

• All cohorts
• Involvement in the planning and/or conduct of the study or previous enrolment in the present study
• Subjects with another malignancy unless curatively treated with no evidence of disease for ≥ 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ, Stage 1, grade 1 endometrial carcinoma. Patients with a history of localized triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease
• Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or cord compression. Subjects with previously treated brain metastases may participate provided they are stable, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Subjects with a history of treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria:
• Measurable disease outside the CNS
• Only supratentorial metastases allowed
• No history of intracranial hemorrhage
• No ongoing requirement for corticosteroids as therapy for CNS disease; anticonvulsants at a stable dose allowed
• No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to Day 1 of the study
• No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study
• Participation in another clinical study with an investigational product during the last 28 days or 5 half-lives prior to study Day 1. Concurrent enrolment in an observational clinical study or the follow-up period of an interventional study is allowed
• Subjects receiving any systemic chemotherapy, radiotherapy, within 4 weeks from the last dose prior to study treatment.
• Receiving, or having received during the four weeks prior to study entry, corticosteroids for any reason. The following are exceptions to this criterion:
• Intranasal, inhaled, topical, or local steroid injections
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent

Sponsors & Collaborators

• University Health Network, Toronto: lead
• AstraZeneca: collaborator

Study Sites (1)

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

MeSH Terms

Conditions

Leiomyosarcoma

Interventions

durvalumab; olaparib; cediranib

Condition Hierarchy (Ancestors)

Neoplasms, Muscle Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma

Study Officials

• Lillian Siu, MD

  Princess Margaret Cancer Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2019
• First Posted: February 22, 2019
• Study Start: April 8, 2019
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027
• Last Updated: February 9, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)