ESCALE: Phase I Dose Escalation Trial of Efavirenz in Solid Tumours or Non-Hodgkin Lymphoma in Therapeutic Failure.

• Sponsor: Institut Bergonié (Other)
• Overall Status: Completed
• CT.gov ID: NCT01878890
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arms: 4
• Actual Duration (Months): 63.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Hypothesis: encouraging results of phase II study FAVE in the treatment of hormonal resistant prostate cancer lead us to continue clinical development of efavirenz. Furthermore, all available pre-clinical and clinical data lead us to conduct a Phase 1 study with efavirenz. Objective of this Phase I is to test doses above 600 mg / day in patients with cancer in order to determine the maximum tolerated dose to improve therapeutic effect.

This study is a single center Phase I trial, conduct with dose escalation scheme of efavirenz by continual reassessment method likehood approach (CRML) on solid tumours (except pancreatic cancer) and non-Hodgkin lymphoma (NHL).

Main objective is to determine the safety profile, and particularly the maximum tolerated dose of efavirenz for the treatment of patients with solid tumors (except pancreatic cancer) or NHL in therapeutic failure.

Secondary objectives are:

• Evaluate efavirenz pharmacokinetics at 2, 4 and 12 weeks;

• Evaluate objective response at 12 weeks;

• Evaluate progression free survival at 6 months;

• Assess biological progression-free survival at 6 months (prostate tumours only).

Primary Endpoint

Safety will be evaluated according to the toxicity scale NCI-CTCAE v4.0. Dose limiting toxicities will be collected during the first 28 days (+ / - 7 days) after first dose of

Efavirenz and will be defined as follows:

• Any drug-related toxicity with grade ≥ 3 according to NCI-CTCAE v4.0 (except alopecia, nausea and vomiting, regardless of grade),

• Any drug-related toxicity, regardless of grade, who led a treatment delay> 14 days,

• Score ≥ 19 HAD during treatment. Secondary Criteria

• Solid tumors: response and progression defined by RECIST v1.1 [Eisenhauer EA et al. EJC 2009).

• Non-Hodgkin lymphomas: Response and progression defined according to Cheson criteria [Cheson BD et al. JCO 1999]

• Biological progression (particular case of prostate tumors): defined according to Scher [Scher HI et al. JCO 2008] Statistical Considerations This is a Phase I dose escalation strategy using the method CRML, described by O'Quigley and Shen [O'Quigley et al. Biometrics 1996] and commonly used in Phase I trials in oncology.

• Maximum number of eligible and evaluable subjects is 30.

• Six dose levels are initially defined: 600 mg, 1200 mg, 1800 mg, 2200 mg, 2600 mg, 3000 mg.

• The risk of dose limiting toxicities maximum allowed is 25%.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors; Non-Hodgkin's Lymphoma	Drug: Efavirenz 600mg; Drug: Efavirenz 1200 mg; Drug: Efavirenz 1800 mg; Drug: Efavirenz 2200 mg	Phase 1

Detailed Description

This is a Phase I dose escalation strategy according to the method described by CRML O'Quigley and Shen [O'Quigley et al. Biometrics 1996] and commonly used in phase I trials in oncology.

Six levels of doses are initially defined: 600 mg, 1200 mg, 1800 mg, 2200 mg, 2600 mg, 3000 mg.

The maximum potential dose-limiting toxicities allowed is 25%.

Dose limiting toxicities will be defined as follows:

• Any drug-related toxicity with grade ≥ 3 according to NCI-CTCAE v4.0 (except alopecia, nausea and vomiting, regardless of grade),

• Any drug-related toxicity, regardless of grade, who led a treatment delay> 14 days,

• Score ≥ 19 HAD during treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Dose Escalation Trial of Efavirenz for Patients With Solid Tumours or Non-Hodgkin Lymphoma in Therapeutic Failure.
• Actual Study Start Date: Sep 5, 2011
• Actual Primary Completion Date: Sep 16, 2014
• Actual Study Completion Date: Dec 31, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Efavirenz: 600 mg Cohort 1 : Participants received 600 mg of Efavirenz (oral / once a day), until progression or toxicity.	Drug: Efavirenz 600mg; Efavirenz 600 mg (oral daily intake)
Experimental: Efavirenz: 1200 mg Cohort 2 : Participants received 1200 mg of Efavirenz (oral / once a day), until progression or toxicity.	Drug: Efavirenz 1200 mg; Efavirenz 1200mg (oral daily intake)
Experimental: Efavirenz: 1800 mg Cohort 3 : Participants received 1800 mg of Efavirenz (oral / once a day), until progression or toxicity.	Drug: Efavirenz 1800 mg; Efavirenz 1800mg (oral daily intake)
Experimental: Efavirenz: 2200 mg Cohort 4 : Participants received 2200 mg of Efavirenz (oral / once a day), until progression or toxicity.	Drug: Efavirenz 2200 mg; Efavirenz 2200mg (oral daily intake)

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Efavirenz [Up to 28 days for each dosing cohort]

   MTD was determined by testing increasing doses up to 3000 mg (oral daily intake). The dose escalation scheme is the continual reassessment method likehood approach (CRML) described by O'Quigley and Shen [O'Quigley et al. Biometrics 1996]. MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in > 25% of participants. A DLT was any drug-related toxicity with grade ≥ 3 according to NCI-CTCAE v4.0 (except alopecia, nausea and vomiting, regardless of grade), any drug-related toxicity, regardless of grade, who led a treatment delay> 14 days, a score ≥ 19 for the Hospital Anxiety And Depression Scale (HAD) during treatment.

2. Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) [Up to 28 days for each dosing cohort]

   A DLT was any drug-related toxicity with grade ≥ 3 according to NCI-CTCAE v4.0 (except alopecia, nausea and vomiting, regardless of grade), any drug-related toxicity, regardless of grade, who led a treatment delay> 14 days, a score ≥ 19 for the Hospital Anxiety And Depression Scale (HAD) during treatment.

Secondary Outcome Measures

1. 12-week Objective Response Rate [up to 3 months after first adminitration of Efavirenz]

   Objective response is defined as complete or partial response (CR, PR) using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Objective reponse rate is calculated as the number of patients with objective reponse divided by the number of alive patients.

2. 12-week Non-progression Rate [Evaluated up to 3 months after first administration of Efavirenz]

   Non progression is defined as complete or partial response (CR, PR) or stable disease (SD), using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Non-progression rate is calculated as the number of alive and progression free patients divided by the number of patients.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria :

1. Patients with solid tumors (except pancreatic cancer) or non-Hodgkin lymphoma

2. Metastatic disease or locally advanced inoperable tumor, not accessible to standard therapy.

3. Male or female ≥ 18 years and <80 years.

4. Tumor assessable by RECIST v1.1, Scher Cheson 2008 or 99.

5. At least 28 days after completion of prior treatment (radiotherapy, systemic chemotherapy or major surgery).

6. Patient who recovered from any prior toxicity ≤ grade 1.

7. WHO 0-1 in the 7 days before inclusion.

8. Neutrophils ≥ 1500/mm3, Platelets ≥ 100 000/mm3.

9. Total bilirubin and serum creatinine within normal limits (≤ 1.5 ULN), creatinine clearance ≥ 40 ml / min.

10. AST / ALT ≤ 1.5 ULN (≤ 5 ULN if liver metastasis).

11. Normal thyroid function.

12. Normal coagulation: TP ≥ 70%.

13. Life expectancy upper than 3 months.

14. HAD score <13.

15. Negative pregnancy test for women likely to be pregnant within 7 days before inclusion.

16. Effective contraception for the duration of treatment (for both sexes in childbearing or reproductive age): mechanic contraception method should always be used in combination with other contraceptive methods (eg, oral or other hormonal contraceptives). Because of long half-life of efavirenz, it is recommended to use adequate contraceptive measures for 12 weeks after stopping treatment with efavirenz.

17. Informed consent signed and dated by the patient or his legal representative before the establishment of any specific procedure to the study.

18. Clinical examination and laboratory tests made within 7 days before enrollment and start of treatment.

19. Initial assessment and radiological CT / or MRI performed within 30 days before enrollment.

20. Patients potentially compliant with treatment and follow-up study.

21. Ability to swallow capsules or tablets.

22. Patients insured by a social security system.

Exclusion Criteria :

1. Patient with pancreatic cancer.

2. Presence of active or symptomatic cerebral localization (known).

3. History of another cancer except:

• cancer occurred more than five years and considered in complete remission

• in situ cervix carcinomas,

• cutaneous basal cell carcinomas.

1. Current major depressive state (screening by HAD scale total score ≥ 13).

2. Patients with history of depressive disorders, suicide attempts, addiction or other psychiatric disorders.

3. Concomitant use of terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, alkaloids of ergot, voriconazole, mixing St. John's Wort.

4. Patients treated with anti-vitamin K. Treatment with low molecular weight heparin are allowed.

5. Known efavirenz hypersensitivity or to any of its excipients.

6. Severe renal impairment.

7. Severe hepatic impairment.

8. Yellow fever vaccine (yellow fever).

9. Pregnant or lactating.

10. Presence of toxicity> 1 according to the criteria CTCAE V4.0, due to prior cancer therapy.

11. Recurrent diarrhea which can interfere with drug absorption capacity.

12. Patient included in another biomedical research on a drug within 30 days of inclusion.

13. Patient who previously participated in this study.

14. Patient, who for reasons psychological, psychiatric, social, family or geographical could not be treated or monitored regularly by the criteria of the study, patients deprived of liberty or under tutorship.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Institut Bergonié	Bordeaux		France	33076

Sponsors and Collaborators

• Institut Bergonié

Investigators

• Study Chair: Guilhem Roubaud, MD, Institut Bergonié

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Institut Bergonié
• ClinicalTrials.gov Identifier: NCT01878890
• Other Study ID Numbers: IB2011-01
• First Posted: Jun 17, 2013
• Last Update Posted: Jan 27, 2021
• Last Verified: Jan 1, 2021

• Keywords provided by Institut Bergonié: Solid tumors (other than pancreas)
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Efavirenz

Study Results

Participant Flow

Arm/Group Title	Efavirenz - 600 mg	Efavirenz - 1200 mg	Efavirenz - 1800 mg	Efavirenz - 2200 mg
Arm/Group Description	Participants received 600 mg of Efavirenz (oral / once a day), until progression or toxicity.	Participants received 1200 mg of Efavirenz (oral / once a day), until progression or toxicity.	Participants received 1800 mg of Efavirenz (oral / once a day), until progression or toxicity.	Participants received 2200 mg of Efavirenz (oral / once a day), until progression or toxicity.
Period Title: Overall Study
STARTED	5	11	4	5
COMPLETED	5	10	4	5
NOT COMPLETED	0	1	0	0

Baseline Characteristics

Arm/Group Title	Efavirenz: 600 mg	Efavirenz: 1200 mg	Efavirenz: 1800 mg	Efavirenz: 2200 mg	Total
Arm/Group Description	Cohort 1 : Participants received 600 mg of Efavirenz (oral / once a day), until progression or toxicity. Efavirenz 600mg: Efavirenz 600 mg (oral daily intake)	Cohort 2 : Participants received 1200 mg of Efavirenz (oral / once a day), until progression or toxicity. Efavirenz 600mg: Efavirenz 1200 mg (oral daily intake)	Cohort 3 : Participants received 1800 mg of Efavirenz (oral / once a day), until progression or toxicity. Efavirenz 600mg: Efavirenz 1800 mg (oral daily intake)	Cohort 4 : Participants received 2200 mg of Efavirenz (oral / once a day), until progression or toxicity. Efavirenz 600mg: Efavirenz 2200 mg (oral daily intake)	Total of all reporting groups
Overall Participants	5	10	4	5	24
Age (years) [Mean (Inter-Quartile Range) ]
Mean (Inter-Quartile Range) [years]	64.4	59.0	66.8	63.4	62.2
Sex: Female, Male (Count of Participants)
Female	2 40%	3 30%	3 75%	1 20%	9 37.5%
Male	3 60%	7 70%	1 25%	4 80%	15 62.5%
Region of Enrollment (participants) [Number]
France	5 100%	10 100%	4 100%	5 100%	24 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Efavirenz
Description	MTD was determined by testing increasing doses up to 3000 mg (oral daily intake). The dose escalation scheme is the continual reassessment method likehood approach (CRML) described by O'Quigley and Shen [O'Quigley et al. Biometrics 1996]. MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in > 25% of participants. A DLT was any drug-related toxicity with grade ≥ 3 according to NCI-CTCAE v4.0 (except alopecia, nausea and vomiting, regardless of grade), any drug-related toxicity, regardless of grade, who led a treatment delay> 14 days, a score ≥ 19 for the Hospital Anxiety And Depression Scale (HAD) during treatment.
Time Frame	Up to 28 days for each dosing cohort

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	All participants who received at least 1 dose of Efavirenz, either at 600 mg, 1200 mg, 1800 mg, or 2200 mg.
Measure Participants	25
Number [mg]	1200

2. Primary Outcome

Title	Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
Description	A DLT was any drug-related toxicity with grade ≥ 3 according to NCI-CTCAE v4.0 (except alopecia, nausea and vomiting, regardless of grade), any drug-related toxicity, regardless of grade, who led a treatment delay> 14 days, a score ≥ 19 for the Hospital Anxiety And Depression Scale (HAD) during treatment.
Time Frame	Up to 28 days for each dosing cohort

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Efavirenz: 600 mg	Efavirenz: 1200 mg	Efavirenz: 1800 mg	Efavirenz: 2200 mg
Arm/Group Description	Cohort 1 : Participants received 600 mg of Efavirenz (oral / once a day), until progression or toxicity.	Cohort 2 : Participants received 1200 mg of Efavirenz (oral / once a day), until progression or toxicity.	Cohort 3 : Participants received 1800 mg of Efavirenz (oral / once a day), until progression or toxicity.	Cohort 4 : Participants received 2200 mg of Efavirenz (oral / once a day), until progression or toxicity.
Measure Participants	5	10	4	5
Count of Participants [Participants]	0 0%	3 30%	1 25%	3 60%

3. Secondary Outcome

Title	12-week Objective Response Rate
Description	Objective response is defined as complete or partial response (CR, PR) using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Objective reponse rate is calculated as the number of patients with objective reponse divided by the number of alive patients.
Time Frame	up to 3 months after first adminitration of Efavirenz

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	All participants who received at least 1 dose of Efavirenz, either at 600 mg, 1200 mg, 1800 mg, or 2200 mg.
Measure Participants	24
Count of Participants [Participants]	0 0%

4. Secondary Outcome

Title	12-week Non-progression Rate
Description	Non progression is defined as complete or partial response (CR, PR) or stable disease (SD), using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Non-progression rate is calculated as the number of alive and progression free patients divided by the number of patients.
Time Frame	Evaluated up to 3 months after first administration of Efavirenz

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	All participants who received at least 1 dose of Efavirenz, either at 600 mg, 1200 mg, 1800 mg, or 2200 mg.
Measure Participants	24
Count of Participants [Participants]	0 0%

Adverse Events

Time Frame	Adverse event data were collected until death or date of the end of study (6 months after the inclusion of the last patient)
Adverse Event Reporting Description	Adverse Events were monitored/assessed without regard to the specific Adverse Event Term.
Arm/Group Title	Efavirenz: 600 mg		Efavirenz: 1200 mg		Efavirenz: 1800 mg		Efavirenz: 2200 mg
Arm/Group Description	Cohort 1 : Participants received 600 mg of Efavirenz (oral / once a day), until progression or toxicity.		Cohort 2 : Participants received 1200 mg of Efavirenz (oral / once a day), until progression or toxicity.		Cohort 3 : Participants received 1800 mg of Efavirenz (oral / once a day), until progression or toxicity.		Cohort 4 : Participants received 2200 mg of Efavirenz (oral / once a day), until progression or toxicity.
All Cause Mortality
	Efavirenz: 600 mg		Efavirenz: 1200 mg		Efavirenz: 1800 mg		Efavirenz: 2200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		11/11 (100%)		4/4 (100%)		5/5 (100%)
Serious Adverse Events
	Efavirenz: 600 mg		Efavirenz: 1200 mg		Efavirenz: 1800 mg		Efavirenz: 2200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/5 (60%)		4/11 (36.4%)		4/4 (100%)		3/5 (60%)
Blood and lymphatic system disorders
Other	1/5 (20%)	1	0/11 (0%)	0	0/4 (0%)	0	0/5 (0%)	0
Gastrointestinal disorders
Other	0/5 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0	1/5 (20%)	1
General disorders
Other	0/5 (0%)	0	2/11 (18.2%)	2	4/4 (100%)	7	2/5 (40%)	3
Hepatobiliary disorders
other	1/5 (20%)	1	0/11 (0%)	0	0/4 (0%)	0	0/5 (0%)	0
Metabolism and nutrition disorders
Other	1/5 (20%)	1	1/11 (9.1%)	1	2/4 (50%)	2	0/5 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Other	1/5 (20%)	1	0/11 (0%)	0	0/4 (0%)	0	0/5 (0%)	0
Nervous system disorders
Other	0/5 (0%)	0	0/11 (0%)	0	0/4 (0%)	0	1/5 (20%)	1
Psychiatric disorders
Other	0/5 (0%)	0	2/11 (18.2%)	2	1/4 (25%)	1	1/5 (20%)	2
Respiratory, thoracic and mediastinal disorders
other	1/5 (20%)	1	0/11 (0%)	0	0/4 (0%)	0	0/5 (0%)	0
Other (Not Including Serious) Adverse Events
	Efavirenz: 600 mg		Efavirenz: 1200 mg		Efavirenz: 1800 mg		Efavirenz: 2200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		11/11 (100%)		4/4 (100%)		5/5 (100%)
Blood and lymphatic system disorders
Not collected	1/1 (100%)	1	2/11 (18.2%)	2	2/4 (50%)	2	0/5 (0%)	0
Eye disorders
Not collected	0/5 (0%)	0	0/11 (0%)	0	0/4 (0%)	0	1/5 (20%)	1
Gastrointestinal disorders
Not collected	4/5 (80%)	7	8/11 (72.7%)	12	3/4 (75%)	4	3/5 (60%)	7
General disorders
Not collected	3/5 (60%)	3	8/11 (72.7%)	11	4/4 (100%)	7	5/5 (100%)	9
Hepatobiliary disorders
Not collected	1/5 (20%)	1	0/11 (0%)	0	0/4 (0%)	0	0/5 (0%)	0
Infections and infestations
Not collected	1/5 (20%)	1	1/11 (9.1%)	1	0/4 (0%)	0	0/5 (0%)	0
Injury, poisoning and procedural complications
Not collected	0/5 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0	0/5 (0%)	0
Investigations
Not collected	0/5 (0%)	0	1/11 (9.1%)	1	0/4 (0%)	0	2/5 (40%)	2
Metabolism and nutrition disorders
Not collected	2/5 (40%)	2	4/11 (36.4%)	4	2/4 (50%)	2	2/5 (40%)	2
Musculoskeletal and connective tissue disorders
Not collected	1/5 (20%)	1	3/11 (27.3%)	3	0/4 (0%)	0	1/5 (20%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Not collected	1/5 (20%)	1	0/11 (0%)	0	0/4 (0%)	0	0/5 (0%)	0
Nervous system disorders
Not collected	2/5 (40%)	2	5/11 (45.5%)	6	0/4 (0%)	0	4/5 (80%)	5
Psychiatric disorders
Not collected	0/5 (0%)	0	6/11 (54.5%)	8	2/4 (50%)	3	5/5 (100%)	12
Respiratory, thoracic and mediastinal disorders
Not collected	3/5 (60%)	3	0/11 (0%)	0	1/4 (25%)	1	0/5 (0%)	0
Skin and subcutaneous tissue disorders
Not collected	0/5 (0%)	0	1/11 (9.1%)	1	1/4 (25%)	2	0/5 (0%)	0
Vascular disorders
Not collected	4/5 (80%)	4	1/11 (9.1%)	1	1/4 (25%)	1	0/5 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.