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TerminatedNCT03345784Updated Feb 20, 2024Results posted

Testing AZD1775 inC Combination With Radiotherapy and Chemotherapy in Cervical, Upper Vaginal and Uterine Cancers

A Phase 1 interventional study of Adavosertib and Cisplatin in Cervical Carcinoma, Endometrioid Adenocarcinoma and Malignant Female Reproductive System Neoplasm, sponsored by National Cancer Institute (NCI). Terminated at 8 sites in 2 countries. Open to female participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-02-20.

Sponsored by National Cancer Institute (NCI) · Phase 1, Interventional, and Treatment

Why this study was terminated
Inadequate accrual rate
Phase
Phase 1
Study type
Interventional
Enrollment
10
Allocation
Not applicable
Ages
18 Years and older
Sex
Female
01

Study summary

This phase I trial studies the side effects and best dose of adavosertib when given together with external beam radiation therapy and cisplatin in treating patients with cervical, vaginal, or uterine cancer. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. External beam radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving adavosertib, external beam radiation therapy, and cisplatin may work better in treating patients with cervical, vaginal, or uterine cancer.

Read the detailed description

PRIMARY OBJECTIVE:

I. To determine the recommended phase II dose (RP2D) and safety profile of adavosertib (AZD1775) in combination with radiotherapy and concurrent cisplatin in patients with gynecological cancers.

SECONDARY OBJECTIVES:

I. To determine the acute and late toxicity of AZD1775 when administered to patients with gynecological cancer in combination with standard radiotherapy and concurrent cisplatin.

II. To evaluate the pharmacodynamic effects of AZD1775 when administered in combination with radiotherapy and concurrent cisplatin (in particular, for the 15 patients treated in an expansion cohort at the RP2D).

III. To obtain preliminary information about the progression-free survival, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or clinical progression, of AZD1775 in combination with standard radiotherapy and concurrent cisplatin in women with gynecological cancer.

OUTLINE: This is a dose-escalation study of adavosertib.

Patients undergo external beam radiation therapy on days 1-5 and receive adavosertib orally (PO) on days 1, 3, and 5 or once daily (QD) on days 1-5 and cisplatin intravenously (IV) over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and then every 4 months for 2 years.

02

Conditions studied

  • Cervical Carcinoma
  • Endometrioid Adenocarcinoma
  • Malignant Female Reproductive System Neoplasm
  • Recurrent Cervical Carcinoma
  • Stage I Uterine Corpus Cancer AJCC v7
  • Stage I Vaginal Cancer AJCC v6 and v7
  • Stage IA Uterine Corpus Cancer AJCC v7
  • Stage IB Cervical Cancer AJCC v6 and v7
  • Stage IB Uterine Corpus Cancer AJCC v7
  • Stage IB2 Cervical Cancer AJCC v6 and v7
  • Stage II Cervical Cancer AJCC v7
  • Stage II Uterine Corpus Cancer AJCC v7
  • Stage II Vaginal Cancer AJCC v6 and v7
  • Stage IIA Cervical Cancer AJCC v7
  • Stage IIB Cervical Cancer AJCC v6 and v7
  • Stage III Cervical Cancer AJCC v6 and v7
  • Stage III Uterine Corpus Cancer AJCC v7
  • Stage III Vaginal Cancer AJCC v6 and v7
  • Stage IIIA Cervical Cancer AJCC v6 and v7
  • Stage IIIA Uterine Corpus Cancer AJCC v7
  • Stage IIIB Cervical Cancer AJCC v6 and v7
  • Stage IIIB Uterine Corpus Cancer AJCC v7
  • Stage IIIC Uterine Corpus Cancer AJCC v7
  • Vaginal Carcinoma
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
Female
Accepts healthy volunteers
No

Inclusion criteria

  • Patients must have one of the following biopsy proven gynecological cancer and a decision to treat with radiotherapy and concurrent cisplatin chemotherapy (RT-CT)

    • Newly diagnosed epithelial carcinoma of the cervix, cT1B-3B, N0/1, M0/1

      • Patient may have small volume metastatic disease in para-aortic or supraclavicular lymph nodes or at other metastatic sites as long as, in the best judgment of the treatment team, a radical course of pelvic radiotherapy is warranted to assure local disease control
    • Newly diagnosed epithelial carcinoma of the upper 1/3 vagina, T1-3, N0/1, M0/1

      • Patient may have small volume metastatic disease in para-aortic or supraclavicular lymph nodes or at other metastatic sites as long as, in the best judgment of the treatment team, a radical course of pelvic radiotherapy is warranted to assure local disease control
    • Newly diagnosed endometrioid adenocarcinoma of the uterus, cT1-3, N0/1, M0 unsuitable for primary surgery because of the extent of local disease; these patients are eligible if a prior decision has been made to treat radically with neoadjuvant chemoradiation followed by surgery or further radiotherapy (including brachytherapy) depending on response
    • Central pelvis or sidewall recurrence of epithelial carcinoma of the cervix of endometrioid adenocarcinoma of the uterus after previous surgery without previous pelvic radiotherapy
  • Patients must be planned to receive whole pelvic radiotherapy to a total dose of 45 Gy or greater
  • Patients must be able to receive weekly cisplatin
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 60%)
  • Life expectancy of greater than 3 months
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9 g/dL

    • Blood transfusions are allowed at any time during the screening, treatment or follow-up period, according to the center recommendations
  • Prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized ratio (INR) =\< 1.5 upper limit of normal (ULN)
  • Total bilirubin: serum bilirubin within normal limits (WNL) or =\< 1.5 x ULN in patients with liver metastases; or total bilirubin =\< 3.0 x ULN with direct bilirubin WNL in patients with documented Gilbert's syndrome
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]): Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x upper limit of normal (ULN) or =\< 5 x ULN if known hepatic metastases
  • Creatinine clearance (CrCl) >= 60 mL/min as calculated by the Cockcroft-Gault method
  • Patients must be able to swallow whole capsules
  • The effects of AZD1775 on the developing human fetus are unknown; the preclinical chromosomal aberrations assays have shown potential to induce chromosomal aberrations; in addition, cisplatin and radiotherapy are known to be teratogenic; for this reason, women of child-bearing potential must agree to use two birth control methods (two barrier methods or a barrier method plus a hormonal method) or abstinence prior to study entry, for the duration of study participation prior to study entry, for the duration of study participation, and for 4 months after coming off study; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
  • Females with child-bearing potential must have had a negative serum pregnancy test result =\< 28 days prior to the first dose of study treatment
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion criteria

Exclusion Criteria:

  • Patients who have received any radiotherapy or chemotherapy for their current gynecological cancer
  • Patients who received prior pelvic radiotherapy for any indication
  • Patients who have a mean resting correct corrected QT (QTc) interval using the Fridericia formula (QTcF) > 470 msec (as calculated per institutional standards) obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart at study entry, or congenital long QT syndrome; AZD1775 should not be given to patients who have a history of Torsades de pointes unless all risk factors contributed to Torsades have been corrected; AZD1775 has not been studied in patients with ventricular arrhythmias or recent myocardial infarction
  • Patients requiring para-aortic radiotherapy
  • Patients who are receiving any other investigational agents or anticancer therapy concurrently or within 4 weeks (i.e. 28 days)
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775 or cisplatin
  • Uncontrolled intercurrent illness including, but not limited to, myocardial infarction within 6 months, congestive heart failure, symptomatic congestive heart failure, unstable angina pectoris, active cardiomyopathy, unstable ventricular arrhythmia, uncontrolled hypertension, uncontrolled psychotic disorders, serious infections, active peptic ulcer disease, active liver disease or cerebrovascular disease with previous stroke, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because AZD1775 and chemoradiation are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD1775 and cisplatin, breastfeeding must be discontinued if the mother is treated with AZD1775 and cisplatin; these potential risks may also apply to other agents used in this study
  • Patients with another uncontrolled malignancy; patients with a previous malignancy, treated curatively and without evidence of disease relapse are eligible
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD1775; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • History of active clinically significant bleeding
  • History of bowel obstruction or malabsorption syndromes (within the last 3 months) which might limit the absorption of the study drug
04

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
10 participants (actual)

Study arms

  • Experimental
    Treatment (radiation therapy, adavosertib, cisplatin)

    Patients undergo external beam radiation therapy on days 1-5 and receive adavosertib PO on days 1, 3, and 5 or QD on days 1-5 and cisplatin IV over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.

    Drug: Adavosertib · Drug: Cisplatin · Radiation: External Beam Radiation Therapy

Interventions

  • DrugAdavosertib

    Given PO

    Also known as: AZD-1775, AZD1775, MK-1775, MK1775

  • DrugCisplatin

    Given IV

    Also known as: Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin

  • RadiationExternal Beam Radiation Therapy

    Undergo external beam radiation therapy

    Also known as: Definitive Radiation Therapy, EBRT, External Beam Radiation, External Beam Radiotherapy, External Beam Radiotherapy (conventional), External Beam RT, external radiation, External Radiation Therapy, external-beam radiation, Radiation, External Beam, Teleradiotherapy, Teletherapy, Teletherapy Radiation

05

What researchers measure

Primary outcomes

  1. Recommended Phase 2 Dose Defined as the Dose Level With < 1/6 Patients With Dose Limiting Toxicities

    To determine the recommended phase II dose (RP2D) and safety profile of AZD1775 in combination with radiotherapy and concurrent cisplatin in patients with gynecological cancers.

    Time frame: Up to week 5

Secondary outcomes

  1. Frequency and Severity of AZD1775 Toxicity Events in Patients With Gynecological Cancer in Combination With Standard RT and Concurrent Cisplatin

    To determine the acute and late toxicity of AZD1775 when administered to patients with gynecological cancer in combination with standard radiotherapy and concurrent cisplatin. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a subanalysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

    Time frame: Up to 2 years

  2. Pharmacodynamic Effects of AZD1775 in Combination With RT and Concurrent Cisplatin

    To evaluate the pharmacodynamic effects of AZD1775 drugs when administered in combination with radiotherapy and concurrent cisplatin. Pharmacodynamic biomarkers will include: pCDC2, Ki67, γH2AX, pH3, and CC3. Associations between pharmacokinetic data with toxicity profiles will be performed primarily using descriptive statistics; however, logistic regression may be used if warranted.

    Time frame: Up to 2 years

  3. Progression-free Survival

    To obtain preliminary information about the progression-free survival of AZD1775 in combination with radiotherapy and concurrent cisplatin in women with locally advanced gynecological cancer. Progression is defined a clinical or radiological using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

    Time frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years

06

Results

Posted Jun 6, 2023
Limitations and caveats
The main limitation of our study is the small number of patients enrolled due to premature closure; yet the study showed the limiting toxicities of this triplet combination.

Participant flow

This study was performed at 5 academic centers in the United States (four sites) and Canada (one site). It enrolled participants from May 2018 to July 2020.

Participant flow — Overall Study
MilestoneTreatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1
Started55
Completed34
Not completed21
Withdrew: Withdrawal by subject21

Outcome measures

PrimaryRecommended Phase 2 Dose Defined as the Dose Level With < 1/6 Patients With Dose Limiting Toxicities

To determine the recommended phase II dose (RP2D) and safety profile of AZD1775 in combination with radiotherapy and concurrent cisplatin in patients with gynecological cancers.

Time frame:
Up to week 5
Reported as:
Count of participants · Participants
Recommended Phase 2 Dose Defined as the Dose Level With < 1/6 Patients With Dose Limiting Toxicities
ParticipantsTreatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1
Recommended Phase 2 Dose Defined as the Dose Level With < 1/6 Patients With Dose Limiting ToxicitiesNANA
SecondaryFrequency and Severity of AZD1775 Toxicity Events in Patients With Gynecological Cancer in Combination With Standard RT and Concurrent Cisplatin

To determine the acute and late toxicity of AZD1775 when administered to patients with gynecological cancer in combination with standard radiotherapy and concurrent cisplatin. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a subanalysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Time frame:
Up to 2 years
Reported as:
Number · events
Frequency and Severity of AZD1775 Toxicity Events in Patients With Gynecological Cancer in Combination With Standard RT and Concurrent Cisplatin
eventsTreatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1
All Grade 1-2 Toxicities4653
Related Grade 1-2 Toxicities3736
All Grade 3-4 Toxicities83
Related Grade 3-4 Toxicities83
SecondaryPharmacodynamic Effects of AZD1775 in Combination With RT and Concurrent Cisplatin

To evaluate the pharmacodynamic effects of AZD1775 drugs when administered in combination with radiotherapy and concurrent cisplatin. Pharmacodynamic biomarkers will include: pCDC2, Ki67, γH2AX, pH3, and CC3. Associations between pharmacokinetic data with toxicity profiles will be performed primarily using descriptive statistics; however, logistic regression may be used if warranted.

Time frame:
Up to 2 years

No measurements were reported for this outcome.

SecondaryProgression-free Survival

To obtain preliminary information about the progression-free survival of AZD1775 in combination with radiotherapy and concurrent cisplatin in women with locally advanced gynecological cancer. Progression is defined a clinical or radiological using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Time frame:
From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years
Reported as:
Count of participants · Participants
Progression-free Survival
ParticipantsTreatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1
4 Months Post Treatment — Alive and progression-free post-treatment34
4 Months Post Treatment — Lost to Follow-Up00
2 Years Post Treatment — Alive and progression-free post-treatment33
2 Years Post Treatment — Lost to Follow-Up01

Adverse events

Collected over 2 years. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 10/4 (0%)1/4 (25%)4/4 (100%)
Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -10/5 (0%)1/5 (20%)5/5 (100%)
Most frequent serious events
Most frequent serious events
EventTreatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1
Grade 3 DiarrheaGastrointestinal disorders1/40/5
Grade 3 Lymphocyte Count DecreasedBlood and lymphatic system disorders0/41/5
Most frequent other events
Showing 10 of 55
Most frequent other events
EventTreatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1
NauseaGastrointestinal disorders4/45/5
DiarrheaGastrointestinal disorders3/44/5
VomitingGastrointestinal disorders1/44/5
FatigueGeneral disorders3/43/5
HypomagnesemiaMetabolism and nutrition disorders3/40/5
ThrombocytopeniaInvestigations3/40/5
AnemiaBlood and lymphatic system disorders3/40/5
AnorexiaMetabolism and nutrition disorders3/41/5
DermatitisInjury, poisoning and procedural complications0/43/5
Abdominal painGastrointestinal disorders2/41/5

Baseline characteristics

Age, Continuous
Age, Continuous(years)Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1Total
Median48 (43 to 78)53 (35 to 63)50.5 (35 to 78)
Sex: Female, Male
Sex: Female, Male(Participants)Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1Total
Female5510
Male000
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1Total
Hispanic or Latino000
Not Hispanic or Latino459
Unknown or Not Reported101
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1Total
American Indian or Alaska Native000
Asian101
Native Hawaiian or Other Pacific Islander000
Black or African American000
White358
More than one race000
Unknown or Not Reported101
Region of Enrollment
Region of Enrollment(participants)Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1Total
Canada213
United States347
ECOG Performance Status
ECOG Performance Status(Participants)Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1Total
0145
1415
Primary Site
Primary Site(Participants)Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1Total
Cervical459
Uterine101
Prior Therapy
Prior Therapy(Participants)Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1Total
Surgery5510
Radiation000

3 further baseline measures are reported on the registry.

07

Study locations

8 sites
  • University of California Davis Comprehensive Cancer Center
    Sacramento, California 95817, United States
  • UCHealth University of Colorado Hospital
    Aurora, Colorado 80045, United States
  • University of Kentucky/Markey Cancer Center
    Lexington, Kentucky 40536, United States
  • Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
    New Brunswick, New Jersey 08903, United States
  • Rutgers Cancer Institute of New Jersey
    New Brunswick, New Jersey 08903, United States
  • Duke University Medical Center
    Durham, North Carolina 27710, United States
  • BCCA-Vancouver Cancer Centre
    Vancouver, British Columbia V5Z 4E6, Canada
  • University Health Network-Princess Margaret Hospital
    Toronto, Ontario M5G 2M9, Canada
08

References and documents

Study documents

  • Protocol and statistical analysis plan · Jun 3, 2020

Documents are hosted by the registry — open the source record to download them.

09

Registry details

Key details

Study ID
NCT03345784
Lead sponsor
National Cancer Institute (NCI)
Responsible party
Sponsor
First posted
Nov 17, 2017
Start date
May 29, 2018
Primary completion
May 10, 2022
Completion
May 10, 2022
Results posted
Jun 6, 2023
Last update
Feb 20, 2024

Study contacts

Stephanie Lheureux
principal investigator · University Health Network Princess Margaret Cancer Center LAO

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
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