DURVALUMAB for Small cell lung cancer (extensive stage) | Advanced or metastatic small-cell lung cancer

Inclusion criteria

• {"criterion_text":"- Pre-screening phase: Provision of written informed consent for pre-screening.\n- Pre-screening phase: Planned or ongoing treatment with carboplatin/cisplatin, etoposide, durvalumab as 1st-line SoC. Pre-screening must begin no later than the start of the 3rd cycle to allow sufficient time for molecular analyses. At a later date, consultation must be sought with the sponsor and central pathology before proceeding.\n- Pre-screening phase: Available radiographic chest and abdominal CT or MRI scans performed up to 42 days before initial first line treatment with carboplatin/cisplatin, etoposide and durvalumab.\n- Pre-screening phase: At least one measurable site of disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.\n- Pre-screening phase: Patient 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.\n- Screening phase: Informed consent and general conditions_Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (European Union [EU] Data Privacy Directive in the EU) must be obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.\n- Screening phase: Informed consent and general conditions_Completed pre-screening with fulfillment of all inclusion and exclusion criteria of pre-screening. Prescreening must have tested positive for homologous recombination deficiency as defined in this protocol at central testing. Positivity is defined as the presence of a BRCA1/2 or other HRR gene class 4 or class 5 mutation or the presence of a GI-Score above a predefined threshold of ≥ 40. For more information, see the Laboratory Manual\n- Screening phase: Informed consent and general conditions_Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.\n- Screening phase: Informed consent and general conditions_Body weight >30 kg.\n- Screening phase: Informed consent and general conditions_Patients must have a life expectancy ≥ 12 weeks.\n- Screening phase: Disease characteristics_Patients must not have radiographic or clinical disease progression while on induction therapy and/or prior to start of study treatment.\n- Screening phase: Informed consent and general conditions_Provision of signed and dated, written ICF for screening prior to any mandatory study-specific procedures, sampling, and analyses.\n- Screening phase: Disease characteristics_Adequate tumor assessment by CT scan or MRI performed within 28 days prior to enrollment. Imaging from the standard of care can be used for inclusion. These must not be older than 28 days prior to planned C5D1. For adequate imaging a slice thickness of 5 mm in CT and 5 mm in MRI with contrast agent should not be exceeded. More detailed information can be found in the Radiology Manual.\n- Screening phase: Prior/concomitant therapy_Patients must have received 4 cycles (21-day cycles) of induction with carboplatin or cisplatin, etoposide and durvalumab completed within 1 to 14 days prior to initiation of study treatment on C5D1. Patients must have received durvalumab at minimum three times during the four induction cycles.\n- Screening phase: Prior/concomitant therapy_Patients who have received a dose reduction of chemotherapy during induction therapy may participate provided that toxicities have recovered at C5D1 as described below.\n- Screening phase: Medical conditions_Adequate organ and marrow function as defined below. a) Haemoglobin ≥10 g/dL b) Absolute neutrophil count (ANC) ≥1.5 × 10E9 /L c) Platelet count ≥100 × 10E9/L d) Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician. e) Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN f) Measured creatinine clearance (CL) >51 mL/min or Calculated creatinine CL>51 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance. Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a serum creatinine (mg/dL) x 72 a where F=0.85 for females and F=1 for males.\n- Screening phase: Reproduction_Before enrollment, a woman must be either: a) Not of childbearing potential: premenarchal; postmenopausal (for definition see protocol section 4.5) b) Of childbearing potential: practicing effective method(s) of birth control consistent with local regulations regarding the use of birth control methods for patients participating in clinical studies (see protocol section 4.5 and Annex 13.1) c) Patients must agree to continue contraception throughout the study and continuing through 6 months after the last dose of study drug. Note: If the childbearing potential changes after start of the study (eg, woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) the woman must begin a highly effective method of birth control, as described above.\n- Screening phase: Reproduction_A woman of childbearing potential must have a negative serum (b-human chorionic gonadotropin [b-hCG]) at Screening. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study drug.\n- Screening phase: Reproduction_A man who is sexually active with a woman of childbearing potential must agree to use a condom with spermicidal foam/gel/film/cream/suppository and his partner must also be practicing a highly effective method of contraception (see section 4.5). If the subject is vasectomized, he must still use a condom (with or without spermicide), but his female partner is not required to use contraception. The subject must also not donate sperm during the study and for 3 months after receiving the last dose of study drug.\n- Screening phase: Informed consent and general conditions_Provision of written informed consent for pre-screening.\n- Screening phase: Informed consent and general conditions_Age ≥ 18 years\n- Screening phase: Informed consent and general conditions_Newly diagnosed, histologically documented advanced or metastatic SCLC (UICC stage III which is not amenable to curative radiochemotherapy or stage IV). Note: Assignment of stage must be done according to the 8th edition of American Joint Committee on Cancer (AJCC)/Union for Interational Cancer Control (UICC) TNM staging system.\n- Screening phase: Informed consent and general conditions_Patient 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.\n- Pre-screening phase: Age ≥ 18 years\n- Pre-screening phase: Newly diagnosed, histologically documented advanced or metastatic SCLC (UICC stage III which is not amenable to curative radiochemotherapy or stage IV). Note: Assignment of stage must be done according to the 8th edition of American Joint Committee on Cancer (AJCC)/Union for Interational Cancer Control (UICC) TNM staging system.\n- Pre-screening phase: Either de novo biopsies collected as part of routine clinical practice or archival tumor samples (taken ≤6 months prior to pre-screening) are acceptable. Information on the criteria for the formalin fixed paraffin embedded (FFPE) material to be sent in can be found in the Laboratory manual."}

Exclusion criteria

• {"criterion_text":"- Pre-screening phase: Induction therapy other than carboplatin/cisplatin, etoposide and durvalumab (for example: carboplatin/cisplatin, etoposide and atezolizumab or chemotherapy without immunotherapy (the administration of one induction cycle without durvalumab is permitted)))\n- Screening phase: Disease related_Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease (SD) for 28 days\n- Screening phase: Disease related_History of leptomeningeal carcinomatosis.\n- Screening phase: Other medical conditions_Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.\n- Screening phase: Other medical conditions_Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy. Exceptions are: a) Alopecia (any Grade) b) Vitiligo (any Grade) c) Hypothyroidism stable on hormone replacement (Grade ≤2) d) Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician e) Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or olaparib may be included only after consultation with the sponsor. f) For special requirements in the laboratory see Point 15 at inclusion criteria. Note: Grading of toxicities must be done according to National Cancer Institute\n- Screening phase: Other medical conditions_History of another primary malignancy. Exceptions are: a) Malignancy treated with curative intent and with no known active disease >5 years before the first dose of study treatment and of low potential risk for recurrence b) Adequately treated non melanoma skin cancer or lentigo maligna without evidence of disease c) Adequately treated carcinoma in situ without evidence of disease d) Curatively treated localized prostate cancer receiving androgen deprivation therapy and considered to have a very low risk of recurrence e) Lobular carcinoma in situ or ductal carcinoma in situ of the breast that is considered completely cured f) Curatively treated in situ cancer of the cervix, ductal carcinoma in situ, Stage 1, grade 1 endometrial carcinoma g) Curatively treated localized breast cancer receiving antihormonal agents and considered to have a very low risk of recurrence.\n- Screening phase: Other medical conditions_Any acute, chronic or uncontrolled medical, mental or psychological condition, which in the opinion of the investigator would not permit the subject to participate in the study, complete the study or understand the patient information. These may include, but are not limited to: a) Uncontrolled infection b) Uncontrolled diabetes c) Uncontrolled major seizure disorder d) Superior vena cava syndrome e) Active, chronic or ongoing infection requiring systemic anti-infective treatment (e.g. tuberculosis). For human immunodeficiency virus (HIV) and viral hepatitis, please see exclusion criteria below. f) Impaired gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study treatment (e.g. uncontrolled ulcerative diseases, uncontrolled nausea, vomiting diarrhea, or malabsorption syndromes) or patients who are unable to swallow g) Impaired oxygenation requiring continuous oxygen supplementation due to another disease than the primary indication h) Intestitial lung disease i) Psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent\n- Screening phase: Other medical conditions_Patient has a history of clinically significant cardiovascular disease including, but not limited to the following: a) Pericarditis b) Recent (within 3 months) myocardial infarction c) Symptomatic congestive heart failure d) Uncontrolled hypertension e) Unstable angina pectoris f) Cardiac arrhythmia g) Pericardial effusion (pericardial effusion considered due to the disease under study is permitted if clinically stable at screening) h) Myocarditis that is clinically unstable i) Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg. unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, electrolyte disturbances, etc.), or patients with congenital long QT syndrome. Every patient must have triple baseline ECG in the screening. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)\n- Screening phase: Other medical conditions_Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: a) Patients with vitiligo or alopecia b) Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement (see above) c) Any chronic skin condition that does not require systemic therapy d) Patients without active disease in the last 3 years may be included but only after consultation with the sponsor e) Patients with celiac disease controlled by diet alone\n- Screening phase: Other medical conditions_History of active primary immunodeficiency\n- Screening phase: Other medical conditions_Patients with myelodysplastic syndrome/ acute myeloid leukaemia or with features suggestive of MDS/AML\n- Pre-screening phase: Radiographic or clinical evidence of progressive disease (PD)\n- Screening phase: Other medical conditions_Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc) at screening. Participants with a past or resolved HBV infection (defined as the presence of anti‑HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.  Participants co-infected with HBV and HCV, or co-infected with HBV and HDV, namely: HBV positive (presence of HBsAg and/or anti HBcAb with detectable HBV DNA); AND  HCV positive (presence of anti-HCV antibodies); OR  HDV positive (presence of anti-HDV antibodies).\n- Screening phase: Other medical conditions_Patient is known to be positive for HIV with 1 or more of the following:  Not receiving highly active antiretroviral therapy (ART)  Had a change in ART within 6 months of the start of screening  Receiving ART that may interfere with study treatment  CD4+ count <350 /mm^3 at screening  AIDS-defining opportunistic infection within 6 months of start of screening  Does not agree to start ART and be on ART >4 weeks plus having HIV viral load <400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV controlled).\n- Screening phase: Other medical conditions_Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: a) Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent c) Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)\n- Screening phase: Other medical conditions_Receipt of live attenuated vaccine within 30 days prior to the first dose of study medication. Note: Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab and up to 90 days after the last dose of durvalumab.\n- Screening phase: Prior/concomitant therapy_Induction therapy other than carboplatin/cisplatin, etoposides and durvalumab (for example: carboplatin/cisplatin, etoposides and atezolizumab or chemotherapy without immunotherapy (the administration of one induction cycle without durvalumab is permitted)).)\n- Screening phase: Prior/concomitant therapy_Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) within 2 weeks prior to first dose of study intervention (for more information, see protocol section 6.6)\n- Screening phase: Prior/concomitant therapy_Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting study drug is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents (for more information, see protocoll section 6.6)\n- Screening phase: Prior/concomitant therapy_Major surgery within 4 weeks of starting study treatment and patients must have recovered from any effects of any major surgery or an anticipated need for major surgery during the study. Note: Local surgery of isolated lesions for palliative intent is acceptable, as long as this does not affect the only target lesion\n- Screening phase: Prior/concomitant therapy_Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).\n- Screening phase: Prior/concomitant therapy_Concurrent enrollment in another clinical study, unless it is an observational (non inverventional) clinical study during the last 4 weeks\n- Pre-screening phase: Concurrent enrollment in another clinical study, unless it is an observational (non inverventional) clinical study.\n- Screening-phase: Prior/concomitant therapy: Other medical conditions_Any concurrent chemotherapy, IP, biologic or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g. hormone replacement therapy) is acceptable\n- Screening phase: Other exclusions_Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy and 6 months after the last dose of olaparib.\n- Screening phase: Other exclusions_Prior randomisation or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.\n- Pre-screening phase: Negative HRD result in a previous pre-screening in this trial.\n- Pre-screening phase: Patients who are unlikely to meet the eligibility criteria for the screening phase of this study (see protocol sections 4.2.2 and 4.3.2).\n- Screening phase: Disease related_Negative HRD result in a previous pre-screening in this trial.\n- Screening phase: Disease related_Radiographic or clinical evidence of PD.\n- Screening phase: Disease related_Patients with symptomatic uncontrolled CNS metastases.  Patients with previously known brain metastases may participate provided they are clinically stable for at least 2 weeks and, have no evidence of new or enlarging brain metastases and also are off steroids ≥ 2 weeks (unless receiving a dose equivalent to prednisone ≤10 mg) prior to dosing with study medication. Stable brain metastases by this definition should be established prior to the first dose of study medication.  Subjects with known untreated, asymptomatic brain metastases (i.e., no neurological symptoms, no requirements for corticosteroids) may participate but will require regular imaging of the brain as a site of disease as described in visit scheduled.\n- Screening phase: Disease related_Radiation therapy and/or surgical procedures must be completed 2 weeks prior to study enrolment."}

Primary endpoints

• {"endpoint_text":"- Progression-free survival (PFS) according to investigator-assessed RECIST 1.1 from start of maintenance therapy","definition_or_measurement_approach":"PFS measured according to investigator-assessed RECIST 1.1 from start of maintenance therapy"}

Secondary endpoints

• {"endpoint_text":"- Incidence, severity and grading of AEs and SAEs, frequency of dose interruptions and reductions","definition_or_measurement_approach":"Safety endpoints using incidence, severity and grading (NCI CTCAE) of AEs and SAEs; frequency of dose interruptions and reductions"}
• {"endpoint_text":"- Objective response rate (best response) of maintenance (ORR), duration of response (DOR) and disease control rate (DCR) according to investigatorassessed RECIST 1.1, immune objective response rate (iORR), immune duration of response (iDOR), immune disease control rate (iDCR), immune progression-free survival (iPFS) according to iRECIST and OS","definition_or_measurement_approach":"Efficacy endpoints assessed by investigator-assessed RECIST 1.1 for ORR/DOR/DCR and by iRECIST for immune endpoints (iORR, iDOR, iDCR, iPFS); OS measured as overall survival"}
• {"endpoint_text":"- PFS, ORR, DOR and DCR according to investigator-assessed RECIST 1.1, iORR, iDOR, iDCR, iPFS according to iRECIST and OS in pre-specified patient subgroups","definition_or_measurement_approach":"Same measurements as above (RECIST 1.1 and iRECIST, OS) evaluated in pre-specified subgroups"}

Germany

Earliest CTIS Part Ii Submission Date

30-07-2024

Latest Decision Or Authorization Date

22-01-2026

Processing Time Days

541

Number Of Sites

5

Number Of Participants

29

Primary sponsor

Full Name

University Of Cologne

Organisation Type

Educational Institution

Country Of Registered Address

Germany

Contract research organisations

Name

SCRATCH Pharmacovigilance GmbH & Co. KG

Responsibilities

sponsorDuties codes: 8; pharmacovigilance (contact: safety-GUIDANCE@scratch-pv.com)

Name

Almac Clinical Services Limited

Responsibilities

sponsorDuties code: 15; Angebotserstellung, Vertragsmanagement (contact: jonathan.cousins@almacgroup.com)

Name

aCROmion GmbH

Responsibilities

sponsorDuties codes: 1,12,5,6 (contact: sabine.kuerpick@acromion-gmbh.com)

Third parties

• {"country":"Germany","full_name":"SCRATCH Pharmacovigilance GmbH & Co. KG","duties_or_roles":"sponsorDuties codes: 8; pharmacovigilance contact email: safety-GUIDANCE@scratch-pv.com","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"sponsorDuties code: 15; value: Angebotserstellung, Vertragsmanagement; contact email: jonathan.cousins@almacgroup.com","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"aCROmion GmbH","duties_or_roles":"sponsorDuties codes: 1,12,5,6; contact email: sabine.kuerpick@acromion-gmbh.com","organisation_type":"Pharmaceutical company"}