A Phase I/II Study of MEDI4736 in Combination with Olaparib in Patients with Advanced Solid Tumors
Zusammenfassung der Studie
This study investigates the investigational drugs MEDI4736 in combination with Olaparib, specifically their efficacy, safety, and effectiveness in preventing the spread of cancer. Additionally, the study examines what happens to the investigational drugs in the body of a participating patient and how well the combination of MEDI4736 and Olaparib is tolerated. Furthermore, it will be assessed whether the immune system of the participating patient is activated by the treatment or if the body produces antibodies (proteins formed by the immune system) against the investigational drugs. Approximately 139 patients (at 24 trial centers in Europe, Asia, and North America) will be enrolled in one of four groups depending on the type of cancer (breast cancer, ovarian cancer, gastric cancer, or lung cancer).
(BASEC)
Untersuchte Intervention
Patients will receive Olaparib during the 4-week initiation treatment period. The dose of Olaparib (in tablet form) is 300 mg twice daily. During the treatment period with the combination of MEDI4736 and Olaparib, patients will receive 300 mg of Olaparib twice daily as well as 1.5 g of MEDI4736 as an infusion every 4 weeks. Patients should receive the study treatment (i.e., MEDI4736 + Olaparib) until there is objective, radiologically confirmed disease progression (assessment performed by the investigator according to the modified RECIST 1.1 criteria), or as long as the patients, in the investigator's opinion, are benefiting from the treatment and do not meet other criteria for discontinuation of treatment.
(BASEC)
Untersuchte Krankheit(en)
advanced solid tumors
(BASEC)
1. Histologically or cytologically confirmed advanced (progressive), metastatic, or recurrent (relapsed) solid tumor (according to the definition below for each tumor type). Only the following tumor types and situations are allowed for inclusion in this study: -- Ovarian carcinoma with gBRCAm (germline BRCA mutation) • Patients with gBRCAm-associated ovarian carcinoma and recurrent disease must have received at least 2 platinum-containing therapies and the carcinoma must be considered platinum-sensitive (recurrence at least 24 weeks after the last platinum therapy). • Patients must have a confirmed germline mutation in the BRCA1 or BRCA2 gene that is believed to be deleterious or probably deleterious (it is known or suspected to be deleterious/lead to loss of function). -- gBRCAm-associated HER2-negative metastatic breast cancer • Patients with gBRCAm-associated HER2-negative breast cancer with metastatic or locally advanced disease that is not surgically removable (or the patient is not a candidate for resection) may have received first, second, or third-line therapy, with all patients needing to meet the following criteria: - Confirmed germline mutation in the BRCA1 or BRCA2 gene that is believed to be deleterious or probably deleterious (it is known or suspected to be deleterious/lead to loss of function). - Prior treatment with an anthracycline (e.g., Doxorubicin, Epirubicin), unless contraindicated, and/or a taxane (e.g., Paclitaxel, Docetaxel), either neoadjuvant/adjuvant or in metastatic disease. - Patients who have previously received platinum-containing chemotherapy are eligible if platinum was administered as a potential curative treatment for an earlier other cancer other than breast cancer (e.g., ovarian carcinoma) and the disease has not been detectable for ≥ 5 years prior to study entry, or if they have received a treatment (adjuvant or neoadjuvant) for breast cancer after or before surgery, provided at least 12 months have elapsed between the last dose of platinum-containing treatment and randomization. - Patients who have received platinum (Cisplatin or Carboplatin either as monotherapy or in combination) for advanced breast cancer may be included in the study if no signs of disease progression occurred during platinum-containing chemotherapy. - Patients with estrogen and/or progesterone receptor-positive disease must have received at least one endocrine therapy (adjuvant or in metastatic disease) and experienced disease progression during that therapy, or they must have a disease for which an endocrine therapy is not considered appropriate by the treating physician. - HER2-negative disease -- Small cell lung cancer • In patients with recurrent SCLC, either early or advanced stage disease is allowed, and a recurrence should have occurred within > 12 weeks after the platinum-containing first-line therapy. If patients have received a second platinum-containing therapy, the same criterion applies (i.e., a recurrence should have occurred > 12 weeks after the second therapy). -- ATM-negative gastric carcinoma • Metastatic or recurrent adenocarcinoma of the stomach (including adenocarcinoma of the esophagogastric junction) with imaging-confirmed progression after first-line therapy: - The first-line regimen must have included a doublet therapy based on 5-fluoropyrimidine and platinum (a triple combination chemotherapy is not permitted). - An acceptable 5-fluoropyrimidine-containing agent is Capecitabine. - A recurrence within 6 months after completion of adjuvant/neoadjuvant chemotherapy with the combination of a 5-fluoropyrimidine and platinum is considered a first-line regimen. - A prior adjuvant/neoadjuvant chemotherapy is allowed if it was completed more than 6 months before the start of first-line therapy. - Gastric tumor with ATM-negative status according to a centrally conducted test during the pre-study phase of this study. Both HER2-positive and negative patients are eligible for inclusion in this study. - Patients with HER2-positive gastric carcinoma must have received treatment with Trastuzumab prior to study entry. 2. At least one measurable lesion that can be accurately determined by computed tomography (CT) (or magnetic resonance imaging [MRI], if a CT is contraindicated) at baseline and is suitable for repeated assessment according to RECIST 1.1. The baseline scan must be performed within 28 days prior to the first dose. A disease determined solely by biomarkers is not considered evaluable. Breast cancers with only bone involvement may be considered on a case-by-case basis at the discretion of the investigator. 3. Male or female patients aged ≥ 18 years (≥ 19 years for South Korea) 4. Eastern Cooperative Oncology Group (ECOG) performance status 0–1 5. Life expectancy ≥ 12 weeks 6. Adequate organ and bone marrow function according to the following: • Absolute neutrophil count (ANC) ≥ 1,500/µl • White blood cell count (WBC) > 3,000/µl • Platelets ≥ 100,000/µl • Hemoglobin (Hb) ≥ 10 g/dl • Total bilirubin ≤ 1.5 × upper limit of normal (ULN), if not due to Gilbert's syndrome • AST (SGOT)/ALT (SGPT) ≤ 2.5 × ULN • Creatinine ≤ 1.5 × within normal range OR • Measured creatinine clearance > 60 ml/min/1.73 m2 • Spontaneous urine protein/creatinine ratio ≤ 1 OR • Protein in 24-hour urine collection ≤ 1,000 mg 7. Ability to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening, or otherwise altering the product formulation. Patients should not have gastrointestinal diseases that would prevent the absorption of the oral drug Olaparib. In the gastric cancer cohort, patients with a complete or partial gastrectomy are allowed. 8. Toxicities from prior therapy (excluding alopecia) should have resolved to ≤ grade 1 according to CTCAE v 4.03 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). Patients with long-standing stable grade 2 neuropathy may be considered after discussion with the investigator. 9. Patients who are willing and able to provide written informed consent prior to any protocol-related procedures, including assessments as part of the screening process, and understand what this entails. 10. Female patients must either be not of childbearing potential (i.e., postmenopausal: age ≥ 60 years and no menstruation for ≥ 1 year without other medical cause, OR prior hysterectomy, OR prior bilateral tubal ligation, OR prior bilateral oophorectomy, OR there must be a negative serum pregnancy test at the time of study entry and the patient must agree to use contraceptive methods if she or her partner is of childbearing potential. 11. For studies regarding BRCA gene mutations, loss of ATM gene, PD-L1 expression, HRD gene testing, and/or other exploratory tumor-based markers, tissue samples must be available. (BASEC)
Ausschlusskriterien
1. Previous chemotherapy or other systemic cancer therapy (eg targeted biological therapy or hormonal agents) within 4 weeks before starting treatment with Olaparib; 6 weeks for nitrosoureas or mitomycin. Exceptions and treatments of particular importance are listed below: • Hormone therapy for estrogen receptor-positive or progesterone-receptor-positive breast cancer is permitted. • Treatment with a test substance within 30 days or 5 half-lives, whichever is longer, prior to enrollment in the study is not permitted. • Previous treatments with biologics that target coregulatory T-cell proteins and / or immune checkpoints are not permitted. Such therapies include, for example: MEDI4736 or other PD1 or PD-L1 inhibitors, or a therapy directed against CTLA4 • Prior treatment with a PARP inhibitor, including Olaparib, is not permitted. 2. Radiation therapy within 4 weeks prior to initiation of treatment with olaparib (including targeted irradiation of bone metastases) or radionuclide therapy within 6 weeks prior to initiation of treatment. 3. Administration of live attenuated vaccine within 30 hours Days before the first dose of MEDI4736. Note: Admitted patients should not receive live vaccines during the study and up to 30 days after the last dose of the investigational medicinal product. 4. Current or prior use of immunosuppressants within 14 days prior to the first dose of MEDI4736 The following exceptions apply to this criterion: • Steroids or local steroid injections administered via the nose, respiratory tract, or the skin (intranasally, inhalatively, or topically) (eg, into a joint [intra-articular]) • Systemic corticosteroids at physiological doses that do not exceed 10 mg of prednisone or equivalent per day • Steroids as premedication for hypersensitivity reactions (eg premedication before CT scans) 5. Current dependence on complete parenteral nutrition or intravenous fluid intake 6. Simultaneous use of medications or agents that are potent inhibitors of cytochrome P450 (CYP) 3A (CYP3A), eg. Ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir, or which are potent inducers of CYP3A4. A list of CYP3A4 inhibitors and inducers can be found in Appendix G. Calcium antagonists of the dihydropyridine type are used to treat a Hypertension allowed. 7. Concomitant therapy with other cancer treatments (other than the use of antihormonal agents in patients with estrogen receptor-positive or progesterone-receptor-positive breast cancer) or long-term use of systemic corticosteroids (except as indicated in exclusion criterion 4). 8. Patients in need of long-acting anesthetics unless they have been treated for adequate pain control within a minimum of 14 days prior to the initiation of the 4-week run-in treatment with olaparib following a stable regimen. 9. Previous donor (allogeneic) bone marrow transplantation or double umbilical cord blood transplantation. 10. Transfusion with whole blood within 120 days prior to enrollment (transfusions with red blood cell concentrate and platelets are acceptable unless administered within 28 days prior to initiation of treatment). 11. Previous allergic reactions associated with substances of similar chemical or biological composition as MEDI4736, Olaparib or other humanized monoclonal antibodies (mAbs). 12. persistent toxicities caused by previous cancer therapy (CTCAE grade ≥ 2), apart from alopecia • It should be noted that patients with evidence of persistent radiotherapy-related complications are not appropriate for this study. 13. Other malignancies within the past 5 years, with the exception of: adequately treated non-melanoma skin cancer, curative carcinoma in situ of the cervix, ductal carcinoma in situ, stage 1, grade 1 endometrial carcinoma or other solid tumors, including curative lymphomas ( without involvement of the bone marrow) without evidence of the disease for ≥ 5 years. Patients with previous localized breast cancer may be eligible if they have completed their adjuvant chemotherapy over 3 years prior to registration and have no recurrent or metastatic disease. 14. Previous leptomeningeal carcinomatosis 15. Known brain metastases or spinal cord compression. In patients with suspected brain metastases at the pre-examination, CT / MRI of the brain should be performed before enrollment in the study. 16. The medical risk of the patient is due to a serious, uncontrolled disease, a non-malignant systemic disease, or due to active uncontrolled Seizures or infections considered poor. These include, for example: • Uncontrolled ventricular arrhythmia (cardiac arrhythmia) • Recently (within 12 weeks) occurred heart attack (myocardial infarction) • Symptomatic congestive heart failure, unstable angina pectoris • Previous thromboembolic events within 12 weeks prior to initiation of 4-week initiation of [run-in] olaparib treatment including stroke (including transient ischemic attack or other central nervous system ischemic events) • Uncontrolled severe seizure disorder • Upper influence congestion • Within the last 2 years previous active diverticulitis, symptomatic gastric ulcer or intraabdominal abscess • signs and / or symptoms of bowel obstruction (current or within 28 days prior to enrollment in the study). • Previous adrenal insufficiency (including patients treated with replacement therapy) • Extensive bilateral pulmonary disease according to high-resolution CT scan • Known or previous clinical diagnosis of tuberculosis • Features of a myelodysplastic syndrome (MDS) or one acute myeloid leukemia (AML) in the peripheral blood smear or bone marrow biopsy at baseline. It should be noted that a bone marrow biopsy is not required for inclusion in the study in the absence of a clinical indication. • No previous or current signs of coagulopathy or haemorrhagic diathesis. Therapeutic anticoagulation for previous thromboembolic events is permitted. 17. Known substance or alcohol abuse 18. Any psychiatric condition that precludes consent 19. Major surgery or significant traumatic injury within the last 2 weeks prior to the start of the 4-week initiation of [run-in] treatment with Olaparib: the patient must have recovered from any effects of major surgery 20. Immunocompromised patients, e.g. B. Patients known to be serologically positive for human immunodeficiency virus (HIV) 21. Hepatitis B virus or hepatitis C virus positive (due to the risk of possible reactivation of the hepatitis virus after steroid administration) 22. Active or previously documented autoimmune or inflammatory diseases (including inflammatory bowel disease [eg colitis or Crohn's disease], (BASEC)
Studienstandort
Lausanne, Zürich
(BASEC)
Sponsor
AstraZeneca AB
(BASEC)
Kontakt für weitere Auskünfte zur Studie
Kontaktperson Schweiz
Dr. Sara Bastian
+41812566668
sara.bastian@clutterksgr.chKantonsspital Graubuenden
(BASEC)
Allgemeine Auskünfte
Abramson Cancer Center, University of Pennsylvania
(ICTRP)
Wissenschaftliche Auskünfte
Abramson Cancer Center, University of Pennsylvania
(ICTRP)
Name der bewilligenden Ethikkommission (bei multizentrischen Studien nur die Leitkommission)
Ethikkommission Zürich
(BASEC)
Datum der Bewilligung durch die Ethikkommission
17.08.2016
(BASEC)
ICTRP Studien-ID
NCT02734004 (ICTRP)
Offizieller Titel (Genehmigt von der Ethikkommission)
A Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination with Olaparib (PARP inhibitor) in Patients with Advanced Solid Tumors (BASEC)
Wissenschaftlicher Titel
A Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination With Olaparib (PARP Inhibitor) in Patients With Advanced Solid Tumors (ICTRP)
Öffentlicher Titel
A Phase I/II Study of MEDI4736 in Combination With Olaparib in Patients With Advanced Solid Tumors. (ICTRP)
Untersuchte Krankheit(en)
OvarianBreastSCLCGastric Cancers (ICTRP)
Untersuchte Intervention
Drug: OlaparibDrug: MEDI4736Drug: Bevacizumab (ICTRP)
Studientyp
Interventional (ICTRP)
Studiendesign
Allocation: Non-Randomized. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)
Ein-/Ausschlusskriterien
Inclusion criteria:
- Patients must have histologically or cytologically confirmed progressive advanced or
metastatic solid tumor of one of the following:
- Platinum sensitive relapsed small cell lung cancer (module 1)
- gBRCAm HER2-negative metastatic breast cancer (module 2)
- gBRCAm ovarian cancer (modules 3 and 5)
- Metastatic or relapsed Gastric cancer (adenocarcinoma) (module 4)
- gBRCAm negative ovarian cancer (modules 6 and 7)
- At least one measurable lesion that can be accurately assessed at baseline by
computed tomography (CT) (or magnetic resonance imaging [MRI] suitable for
assessment as per RECIST 1.1. The baseline scan must be obtained within 28 days
prior to the first dose of olaparib.
- Male or female patients, age =18 years (=19 years for South Korea)
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Life expectancy =12 weeks
- Adequate organ and marrow function
- Ability to swallow oral medications (capsules and tablets) without chewing,
breaking, crushing, opening or otherwise altering the product formulation. Patients
should not have gastrointestinal illnesses that would preclude the absorption of
olaparib, which is an oral agent. For the gastric cancer cohort, patients with a
full or partial gastrectomy will be permitted.
- Ability of patient to understand and the willingness to sign a written informed
consent document prior to any protocol related procedures, including screening
evaluations.
- Female patients must either:
- Be of non-reproductive potential OR
- Have a negative serum pregnancy test within 28 days of study treatment and
confirmed prior to treatment on Day 1, and agree to use contraception if they
or their partner are of reproductive potential
Exclusion criteria
- Prior chemotherapy or other systemic anticancer therapy within 4 weeks prior to
start of olaparib treatment, 6 weeks for nitrosoureas or mitomycin. Exceptions
include: Anti-hormonal treatment for ER positive or PR positive breast cancer is
allowed until 7 days prior to treatment with olaparib, exposure to an
investigational agent within 30 days or 5 half-lives (whichever is the longer) prior
to start of olaparib treatment is not allowed, prior receipt of biologics targeting
T cell co-regulatory proteins and/or immune checkpoints is not allowed. Examples
include MEDI4736 or other PD1 or PD-L1 or PD-L2 inhibitors or anti-CTLA4 therapy,
previous treatment with a PARP inhibitor, is not allowed.
- Radiation therapy within 4 weeks prior to start of olaparib treatment (includes
radiation targeting bone metastases) or radionuclide treatment within 6 weeks of
treatment start.
- Current dependency on total parenteral nutrition or IV fluid hydration.
- Concomitant use of known strong cytochrome P450 (CYP) 3A (CYP3A) inhibitors or
moderate CYP3A inhibitors. Concomitant use of known strong or moderate CYP3A
inducers.
- Concomitant therapy with any other anticancer therapy or chronic use of systemic
corticosteroids.
- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation
- Whole blood transfusions in the last 120 days
- Patients with symptomatic or uncontrolled brain metastases.
- Patients being considered at poor medical risk due to a serious, uncontrolled
medical disorder or non-malignant systemic disease.
- Any psychiatric disorder that prohibits obtaining informed consent
- Major surgery or significant traumatic injury within 2 weeks of run-in
- Immunocompromised patients
- QTc prolongation >470 msec or other significant ECG abnormality noted within 14 days
of treatment
- Pregnant and breastfeeding women are excluded.
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)
- Previous enrolment in the present study
- Participation in a clinical study within 28 days or 5 half-lives of the drug,
whichever is longer. (ICTRP)
nicht verfügbar
Primäre und sekundäre Endpunkte
Initial Stage Cohorts: Disease Control Rate (DCR) at Week 12;Second Stage Cohort: Objective Response Rate (ORR);Second Stage Cohorts: DCR at Week 24 (ICTRP)
Second Stage Expansion Cohort: DCR at Week 24;Initial Stage Cohorts: DCR at Week 28;Second Stage Cohorts: DCR at Week 56;Initial and Second Stage Cohorts: ORR;Initial and Second Stage Cohorts: Duration of Response (DoR);Initial and Second Stage Cohorts: Progression-Free Survival (PFS);Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28;Second Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 24 and 56;Initial and Second Stage Cohorts: Best Percentage Change From Baseline in Target Tumor Size;Initial and Second Stage Cohorts: Time to Study Treatment Discontinuation or Death (TDT);Initial and Second Stage Cohorts: OS;Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736;Initial and Second Stage Cohorts: Serum Concentrations of Olaparib;Second Stage Cohort: Serum Concentrations of Bevacizumab;Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 (ICTRP)
Registrierungsdatum
nicht verfügbar
Einschluss des ersten Teilnehmers
nicht verfügbar
Sekundäre Sponsoren
Iqvia Pty Ltd (ICTRP)
Weitere Kontakte
Susan Domchek, MD, Abramson Cancer Center, University of Pennsylvania (ICTRP)
Sekundäre IDs
2015-004005-16, D081KC00001 (ICTRP)
Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten
nicht verfügbar
Weitere Informationen zur Studie
https://clinicaltrials.gov/ct2/show/NCT02734004 (ICTRP)
Ergebnisse der Studie
Zusammenfassung der Ergebnisse
nicht verfügbar
Link zu den Ergebnissen im Primärregister
nicht verfügbar