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NSCLCPhase 1olaparibNCT01562210

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

A Phase 1 study testing Olaparib, Cisplatin and Radiation in people with NSCLC, run by The Netherlands Cancer Institute at 1 site in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
NSCLC
What is being tested?
Olaparib, Cisplatin and Radiation
Could I receive a placebo?
No, everyone receives an active treatment
How many people
28 participants
Where
1 siteNetherlands
Study dates
Apr 2012to 13 Mar 2020
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • ≥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
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  • 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.

Who cannot join

  • 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
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  • 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

Trial locations and contacts

1 site in 1 country.

Netherlands1 site

  • Netherlands Cancer Institute - Antoni van Leeuwenhoek Ziekenhuis (NKI-AVL)

    Amsterdam, North Holland, 1066 CX

Other trials in Netherlands

About this study

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

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.

Read the 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.

Conditions
NSCLC
Keywords
NSCLC, Olaparib, CCRT

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • OlaparibDrug

    Also called AZD2281

    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.

  • CisplatinDrug

    Also called L01XA03

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

  • RadiationRadiation

    A total dose of 66 Gy will be given in 24 fractions from week 1 to 5, excluding the weekends.

Study groups in NCT01562210
Study groupRoleWhat they receive
Olaparib, radiation +/- CisplatinExperimentalOlaparib and radiotherapy with or without Cisplatin
Receives: Drug: Olaparib; Drug: Cisplatin; Radiation: Radiation

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The incidence of dose limiting toxicities (DLTs)

    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.

    Measured: from start until 3 months after the last RT day

Secondary outcomes (7)

  1. Additional safety variables

    (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.

    Measured: until 5 years after treatment

  2. Objective tumor response

    Measured: until 5 years after treatment

  3. Locoregional control rate (LRCR)

    Measured: at one year

  4. Progression free survival

    Measured: until 5 years after treatment

  5. Pharmacokinetic variables

    AUC, Cmax, Cmin

    Measured: week -1 (baseline) until week 11

  6. Pharmacodynamic variables

    PARP inhibition, γH2AXfoci formation

    Measured: week -1 (baseline) until week 8

  7. Surrogate biomarkers for antitumor response

    metabolic response determined by FDG-PET/CT-imaging, change in circulating tumor cells, molecular/biological parameters (tumor markers)

    Measured: until 5 years after treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Mar 2012 (estimated)
  2. Study startApr 2012
  3. Primary completionMay 2019
  4. Study completion13 Mar 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
28 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01562210
Sponsor's protocol ID
NL35195.031.11
Other IDs
N11ORL
Acronym
olaparib
Status last verified
Mar 2020
First submitted
22 Mar 2012
Last updated
17 Mar 2020
Results posted
No
Data monitoring committee
No

Publications

  • van Werkhoven E, Hinsley S, Frangou E, Holmes J, de Haan R, Hawkins M, Brown S, Love SB. Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples. BMC Med Res Methodol. 2020 Jun 22;20(1):162. doi: 10.1186/s12874-020-01012-z.

    PubMed 32571298

  • de Haan R, van Werkhoven E, van den Heuvel MM, Peulen HMU, Sonke GS, Elkhuizen P, van den Brekel MWM, Tesselaar MET, Vens C, Schellens JHM, van Triest B, Verheij M. Study protocols of three parallel phase 1 trials combining radical radiotherapy with the PARP inhibitor olaparib. BMC Cancer. 2019 Sep 10;19(1):901. doi: 10.1186/s12885-019-6121-3.

    PubMed 31500595

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Olaparib, Cisplatin and Radiation in people with NSCLC, run by The Netherlands Cancer Institute at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 17 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The incidence of dose limiting toxicities (DLTs) (time frame: from start until 3 months after the last RT day). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01562210, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Mar 2020.

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