Olaparib Dose Escalating Trial + Concurrent RT With or Without Cisplatin in Locally Advanced NSCLC

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2013 by The Netherlands Cancer Institute
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
The Netherlands Cancer Institute
ClinicalTrials.gov Identifier:
NCT01562210
First received: March 22, 2012
Last updated: June 25, 2013
Last verified: June 2013
  Purpose

Phase I dose escalating trial. Primary objective of this study is to define the maximal tolerated dose (MTD)of Olaparib in combination with high dose radiotherapy with or without daily dose Cisplatin in locally advanced NSCLC. Secondary objectives include to define safety profile, determine PK/Pd variables and document preliminary evidence of objective tumor response.


Condition Intervention Phase
NSCLC
Drug: Olaparib
Drug: Cisplatin
Radiation: Radiation
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Olaparib Dose Escalating Trial in Patients Treated With Radiotherapy With or Without Daily Dose Cisplatin for Locally Advanced Non-small Cell Lung Carcinoma

Resource links provided by NLM:


Further study details as provided by The Netherlands Cancer Institute:

Primary Outcome Measures:
  • The incidence of dose limiting toxicities (DLTs) [ Time Frame: from start until 3 months after the last RT day ] [ Designated as safety issue: Yes ]
    The incidence of dose limiting toxicities occuring during the DLT evaluation period (from start of study treatment until 3 months after the last radiation day). This endpoint will be used to determine the maximal tolerated dose of Olaparib in combination with radiotherapy with and without low dose Cisplatin.


Secondary Outcome Measures:
  • Additional safety variables [ Time Frame: until 5 years after treatment ] [ Designated as safety issue: Yes ]
    (S)AE's, laboratory parameters, vital signs, lung function, long term toxicity: defined as grade ≥ 2 toxicity (with a special attention for pulmonary and esophageal toxicity) that is possibly, probably or definitely related to study treatment, occurring or persisting from 3 months after the last irradiation day until 5 years after treatment.

  • Objective tumor response [ Time Frame: until 5 years after treatment ] [ Designated as safety issue: No ]
  • Locoregional control rate (LRCR) [ Time Frame: at one year ] [ Designated as safety issue: No ]
  • Progression free survival [ Time Frame: until 5 years after treatment ] [ Designated as safety issue: No ]
  • Pharmacokinetic variables [ Time Frame: week -1 (baseline) until week 11 ] [ Designated as safety issue: No ]
    AUC, Cmax, Cmin

  • Pharmacodynamic variables [ Time Frame: week -1 (baseline) until week 8 ] [ Designated as safety issue: No ]
    PARP inhibition, γH2AXfoci formation

  • Surrogate biomarkers for antitumor response [ Time Frame: until 5 years after treatment ] [ Designated as safety issue: No ]
    metabolic response determined by FDG-PET/CT-imaging, change in circulating tumor cells, molecular/biological parameters (tumor markers)


Estimated Enrollment: 60
Study Start Date: April 2012
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Olaparib, radiation +/- Cisplatin
Olaparib and radiotherapy with or without Cisplatin
Drug: Olaparib

Olaparib will be given orally BID for 36 days, administrated with a 12 hour interval. Olaparib will start 2 days before RT and will continue for 2 days after the last RT fraction. Olaparib is also given during the non-radiotherapy days but no maintenance treatment is given after radiotherapy is finished.

The first cohort will receive Olaparib with a dose of 25mg BID combined with Cisplatin and RT. Thereafter in both with and without cisplatin arms dose escalation will follow to 50mg, 100mg, 200mg, 300mg and 400mg BID.

Other Name: AZD2281
Drug: Cisplatin
6 mg/m2 (5 days/week), 1-1.5 hr before the irradiation (week 1 to 5), given as a 5-minutes intravenous infusion.
Other Name: L01XA03
Radiation: Radiation
A total dose of 66 Gy will be given in 24 fractions from week 1 to 5, excluding the weekends.

Detailed Description:

Concurrent chemoradiotherapy (CCRT) is the treatment of choice for patients with locally advanced NSCLC. The cure rates however need to be improved. The main mechanism by which both radiation and Cisplatin kill tumor cells is by an accumulation of un- or misrepaired DNA damage.PARP inhibitors increase radiation and chemotherapy (Cisplatin) response in preclinical studies including lung cancer models.

This open label dose escalating trial consists of a screening phase, a treatment phase and a follow up phase.

The screening phase: patients who can tolerate concurrent cisplatin will receive Olaparib, RT and Cisplatin. Patients who can not tolerate concurrent cisplatin will receive Olaparib and RT with or without prior sequential chemotherapy.

The treatment phase:dose escalation of Olaparib will be performed in cohorts of 3 subjects. The decision to escalate to the next dose level will be based on the occurrence of DLTs during the DLT evaluation period (i.e. 3 months following the last day of irradiation) and will be made after all patients within the cohort have completed their third month of follow up.

Active follow-up phase: frequent follow up will take place during the first 3 months (acute toxicity). Thereafter patients will be monitored for late toxicity and for disease activity 3-monthly throughout the first year and thereafter 6-monthly until 5 years, when patients are deemed to be cured and follow up is no longer warranted.

Olaparib will be given orally BID for 36 consecutive days, administrated with a 12 hour interval. Olaparib will start 2 days before start of RT and will continue for 2 days after the last RT fraction. Olaparib is also given during the non-radiotherapy days but no maintenance treatment is given after radiotherapy is finished.

Radiotherapy (for all patients): a total dose of 66Gy will be given in 24 fractions from week 1 to 5.

Cisplatin (concurrent chemoradiotherapy): daily dose Cisplatin 6mg/m2 (5 days/week), 1-1.5 hr before the irradiation (week 1 to 5), given as a 5-minutes intravenous infusion.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • ≥18 years of age
  • Histologically or cytologically confirmed diagnosis of NSCLC
  • Stage II/III non-operable disease, without malignant pleural effusion
  • Presence of at least one measurable target lesion
  • Acceptable pulmonary function as defined by a Fev1 of ≥30% and a DLCO of ≥ 40% of predicted,
  • NYHA I-II functional status
  • Expected risk of radiation-induced pulmonary toxicity is modest: MLD ≤ 20 and maximum cord dose 50 Gy
  • WHO performance 0-1
  • Life expectancy of at least 6 months
  • Adequate hematological, renal and hepatic functions

    • Hemoglobin ≥ 5.5 mmol/l
    • Leucocytes > 3.0 x 109/l
    • Absolute neutrophil count > 1.5x109/l
    • Platelet count > 100 x 109/l
    • Total bilirubin < 1.5 x UNL
    • ASAT/ALAT < 2.5 x UNL
    • Alkaline phosphatase < 5 x UNL
    • Creatinine < 130 mmol/l or creatinine clearance > 50 ml/min; measured or calculated
    • Urine dipstick for proteinuria < 2+. If urine dipstick is ≥ 2, 24 hour urine must demonstrate < 500 mg of protein in 24 hours
  • No pre-existing sensory neurotoxicity grade ≥ 1 (CTCAE)
  • Patients of reproductive potential must agree to practice two effective medically approved contraceptive method during the trial and 3 months afterwards
  • Signed written informed consent.

Exclusion Criteria:

  • Concurrent active malignancy other than localized, non-melanoma skin cancer or carcinoma-in-situ of the cervix (unless definitive treatment was completed 5 years or more before study entry and the patient has remained disease free)
  • Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents within the 3 weeks prior to start of therapy (or a longer period depending on the defined characteristics of the agents used e.g. 6 weeks for mitomycin or nitrosourea). Patients may continue the use of LHRH agonists for cancer; bisphosphonates for bone disease and corticosteroids.
  • Patients, selected for sequential chemoradiotherapy, are excluded if no disease control (all responses except progression) is obtained after induction chemotherapy.
  • Prior:

    • Ipsilateral radiotherapy to the chest;
    • Chemotherapy for other indications than NSCLC within the last 5 years
  • History of interstitial pneumonitis (to include diffuse alveolar damage, non-malignant causes of pneumonitis, ARDS, alveolitis, cryptogenic organising pneumonia, obliterative bronchiolitis, non-malignant causes of pulmonary fibrosis, eligibility based on the judgement of the primary investigator), active infection on day of enrolment
  • Significant cardiovascular disease as defined by:

    • History of congestive heart failure requiring therapy;
    • History of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry;
    • Presence of severe valvular heart disease;
    • Presence of a ventricular arrhythmia requiring treatment;
    • Uncontrolled hypertension
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial.
  • Participation in other trial with investigational drug or treatment modality
  • Co-existing serious active infection requiring parenteral antibiotics
  • Patients with hepatic disease e.g. patients with known serologically positive Hepatitis B or Hepatitis C as they may be more at risk of toxicity from Olaparib
  • Immunocompromised patients e.g. human immunodeficiency virus (HIV)
  • Myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML on peripheral blood smear.
  • Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study
  • Gastrointestinal disorders that may interfere with absorption of the study drug or patients who are not able to take oral medication
  • Concomitant medications:

    • Any previous treatment with a PARP inhibitor, including Olaparib
    • Patients receiving the following classes of inhibitors of CYP3A4 (see Section 7.4 for guidelines and wash out periods)

      • Azole antifungals
      • Macrolide antibiotics
      • Protease inhibitors
  • Persistent grade 2 or greater toxicities, from any cause
  • Pregnant or breast-feeding women
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01562210

Contacts
Contact: Marcel Verheij, MD, PhD 0031-20-5122153 m.verheij@nki.nl
Contact: Michel M. van den Heuvel, MD, PhD 0031-20-5122924 m.vd.heuvel@nki.nl

Locations
Netherlands
Netherlands Cancer Institute - Antoni van Leeuwenhoek Ziekenhuis (NKI-AVL) Recruiting
Amsterdam, Noord-Holland, Netherlands, 1066 CX
Principal Investigator: M. M. van den Heuvel, MD, PhD         
Principal Investigator: M. Verheij, MD, PhD         
Sponsors and Collaborators
The Netherlands Cancer Institute
AstraZeneca
Investigators
Principal Investigator: Marcel Verheij, MD, PhD Antoni van Leeuwenhoekziekenhuis (NKI-AVL)
Principal Investigator: Michel M. van den Heuvel, MD, PhD Antoni van Leeuwenhoekziekenhuis (NKI-AVL)
  More Information

No publications provided

Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT01562210     History of Changes
Other Study ID Numbers: NL35195.031.11, N11ORL
Study First Received: March 22, 2012
Last Updated: June 25, 2013
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by The Netherlands Cancer Institute:
NSCLC
Olaparib
CCRT

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Cisplatin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on October 16, 2014